WO2024178151A2 - Peptides kibra et leurs utilisations - Google Patents

Peptides kibra et leurs utilisations Download PDF

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WO2024178151A2
WO2024178151A2 PCT/US2024/016770 US2024016770W WO2024178151A2 WO 2024178151 A2 WO2024178151 A2 WO 2024178151A2 US 2024016770 W US2024016770 W US 2024016770W WO 2024178151 A2 WO2024178151 A2 WO 2024178151A2
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kibra
terminal
amino acid
acid sequence
peptide
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WO2024178151A3 (fr
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Tara TRACY
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Buck Institute for Research on Aging
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Buck Institute for Research on Aging
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • BACKGROUND The dynamic function of synapses is critical for encoding memories in the brain.
  • Pathogenic tau obstructs glutamatergic synapse function by blocking long-term potentiation (LTP), representing a key mechanism underlying memory impairment in tau-associated memory deficit disorders, for example Alzheimer’s disease.
  • LTP long-term potentiation
  • BRIEF SUMMARY In an aspect is provided a method of treating a tau-associated memory deficit disorder in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a C-terminal KIBRA compound.
  • a method of treating aging-associated cognitive decline in a subject in need thereof including administering to the subject a therapeutically effective amount of a C-terminal KIBRA compound.
  • a C-terminal KIBRA compound including the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, wherein (a) at least one of the amino acids of the C-terminal KIBRA peptide is a non-natural amino acid analog; and/or (b) the C-terminal KIBRA compound further includes a TAT amino acid sequence, a penetratin amino acid sequence, an oligoarginine amino acid sequence, a xentry amino acid sequence, a transportan amino acid sequence, a cyclic-TAT amino acid sequence, a cyclic penetratin amino acid sequence, a cyclic oligoarginine amino acid sequence, a cyclic x
  • FIGS.1A-1F shows that CT-KIBRA reverses the impairment of activity-dependent postsynaptic AMPAR trafficking and LTP caused by pathogenic tau.
  • FIG.1A shows the design of full-length KIBRA and truncated KIBRA constructs fused to a flag tag.
  • NT-KIBRA contained the first 86 residues and CT-KIBRA included the last 187 residues of KIBRA.
  • FIG. 1D shows TauKQ and ntg mice were injected with control empty vector lentivirus or CT-KIBRA lentivirus at 15-16 months old.
  • Field recordings were performed in the dentate gyrus molecular layer of brain slices from mice at 17-18 months of age.
  • the field excitatory postsynaptic potentials (fEPSP) slopes and the fiber volley (FV) amplitudes were measured in response to increasing stimulus intensities applied to the perforant pathway inputs.
  • TauKQ high mouse brain slices exhibited significantly increased mean FV amplitude in dentate gyrus at the highest stimulus intensities (20 ⁇ A stimulus: ntg lenti-control vs.
  • FIG.1E shows representative traces of fEPSPs recorded in the dentate gyrus before and after TBS of the perforant pathway to induce LTP in dentate granule cells. Quantification of the fEPSP slopes 20 min before and 60 min after TBS was normalized to the average fEPSP slope during the first Scale bars, 0.4 mV and 10 ms.
  • FIG.1F is a graph of the mean fEPSP slopes at 55-60 min after mice/group; *p ⁇ 0.05, **p ⁇ 0.01, one-way ANOVA, Bonferroni post-hoc analyses). Values are given as means ⁇ SEM.
  • FIGS.2A-2L shows that CT-KIBRA expression in hippocampus reverses memory impairment in tauKQhigh mice despite pathological tau accumulation and CA1 synapse loss.
  • FIG.2A shows that during the sample phase, the mean proportion of time that the mice spent exploring two identical objects in each context was calculated. Each mouse explored the identical X1 and X2 objects in Context 1, and the identical Y1 and Y2 objects in Context 2 which were distinct from the objects in Context 1.
  • FIG.2B shows the mean percent time spent exploring the incongruent and congruent objects in both contexts for each group was analyzed during the test phase of the object-context discrimination test (*p ⁇ 0.05, paired Student’s t-test).
  • FIG.2D shows the mean distance travelled to the hidden platform and the average swim velocity were measured during hidden platform training (p > 0.05, repeated measures two-way ANOVA).
  • FIG. 2E shows representative swim paths of mice during the probe trials for spatial memory testing performed at 24 h and 7 days after hidden platform training.
  • FIG.2H shows an illustration of a mouse hippocampus depicting where the imaging of mossy fibers in CA3 (h) and the imaging of synapses in CA1 (l) was performed.
  • FIG.2J shows representative immunoblots of phosphorylated tau (AT180 and AT270 antibodies), human tau (HT7 antibody), and total tau (Tau5 antibody) from hippocampal homogenates of ntg lenti-control, tauKQhigh lenti-control and tauKQhigh lenti-CT-KIBRA mice.
  • FIGS.3B-3D shows that HA-PKM ⁇ and CT- KIBRA-flag expression constructs were transfected into HEK293 cells. One day later, the cells were treated with cycloheximide (CHX) to inhibit translation for 24 or 48 h.
  • CHX cycloheximide
  • FIG.3B shows immunoblots of HA-PKM ⁇ , CT-KIBRA-flag and GAPDH from HEK cells treated with CHX to monitor PKM ⁇ degradation.
  • FIG.3D shows a graph showing HA-PKM ⁇ stability in HEK293 cells with or without CT-KIBRA-flag co-expression.
  • FIGS.4A-4F shows that CT-KIBRA-induced resilience to tau-mediated synaptic and memory deficits is associated with higher PKM ⁇ levels.
  • FIG.4B shows representative immunoblots of PKM ⁇ , PSD-95, and GAPDH from hippocampal homogenates of three individual ntg lenti- control, taukQhigh lenti-control and taukQhigh lenti-CT-KIBRA mice.
  • FIGS.5A-5E shows that CT-KIBRA restores AMPAR trafficking during LTP by interacting with PKM ⁇ in neurons with pathogenic tau.
  • FIG.5D shows a graph of the quantification of surface GluA1 immunofluorescence in spines of tauKQ-expressing neurons showing that cLTP- induced postsynaptic receptor insertion is re-established by CT-KIBRA, but not CT-KIBRA- AAA.
  • FIG.5E shows a model depicting the impact of KIBRA and PKM ⁇ on postsynaptic AMPAR trafficking LTP in healthy conditions (left) and in tauopathy (middle). Expression of CT-KIBRA in tauopathy neurons (right) with high pathogenic acetylated tau levels can restore postsynaptic AMPAR recruitment during plasticity, which mechanistically involves the interaction between CT-KIBRA and PKM ⁇ .
  • FIGS.6A-6K shows that reduced KIBRA levels in human brain and increased KIBRA levels in human CSF correlate with pathological tau levels and cognitive impairment in tauopathy.
  • FIG.6A shows Immunoblot analyses of soluble homogenates from the middle temporal gyrus region of human brain from control, Alzheimer’s disease and Pick’s disease cases. Of the 20 cases analyzed, 12 were assigned a Clinical Dementia Rating (CDR) sum of boxes score based on cognitive function that are labeled above each lane.
  • FIGS.6D-6E show graphs of quantified (FIG.6D) KIBRA and (FIG.6E) PKM ⁇ levels in brain homogenate from the 12 cases that were assigned CDR scores (8 of the 20 brain samples used for this study were not assigned CDR scores).
  • FIGS.6H- 6J show Spearman correlation analyses show the relationship between KIBRA levels and (FIG.
  • MMSE Mini-mental State Exam
  • FIGS.8B-8C show Gene Set Enrichment Analysis (GSEA) on the proteins identified that were downregulated in tauKQ high lenti-control mice (FIG. 8B) and tauKQ high lenti-CT-KIBRA mice (FIG.8C) compared to controls.
  • GSEA Gene Set Enrichment Analysis
  • FIG.8D show ClueGO cellular component enrichment of proteins that were upregulated in hippocampus of tauKQ high mice with or without CT-KIBRA expression compared to ntg lenti-control mice. Node colors denote grouped networks (p ⁇ 0.0005).
  • FIG.9 shows that PICK1 interacts more with full-length KIBRA than the truncated KIBRA variants related to FIG.3.
  • FIGS.10A-10D show that PKM ⁇ and PICK1 levels in hippocampus of tauKQ high mice related to FIG.4.
  • FIG.10A shows immunoblots of PKM ⁇ , PSD-95 and GAPDH from hippocampal lysates of three non-transgenic (ntg) and three tauKQ high mice that did no receive training in behavioral tests of hippocampal-dependent learning and memory.
  • FIG.10A shows immunoblots of PKM ⁇ , PSD-95 and GAPDH from hippocampal lysates of three non-transgenic (ntg) and three tauKQ high mice that did no receive training in behavioral tests of hippocampal-dependent learning and memory.
  • FIG.10B shows graphs of PKM ⁇ levels relative
  • FIG. 10C shows immunoblots of PICK1 and GAPDH from hippocampal lysates of three mice from ntg lenti-control, tauKQ high lenti-control, and tauKQ high lenti-CT-KIBRA grops that underwent training in learning and memory tests.
  • FIGS.11A-11B show that expression of HA-PKM ⁇ and CT-KIBRA constructs in cultured hippocampal neurons related to FIG.5.
  • FIGS.12A-12D show that human KIBRA detection by ELISA and CSF KIBRA relative to phosphorylated tau and A ⁇ related to FIG.6.
  • FIG.12A shows ELISA-based detection of KIBRA levels from lysates of HEK293 cells transfected with a human KIBRA construct (red) and untransfected control HEK293 cells (black).
  • FIG.12B shows the quantification of the concentration of KIBRA protein detected in cerebrospinal fluid (CSF) of human subjects that had either normal ( ⁇ 61 pg/mL) or high (> 61 pg/mL) levels of phosphorylated tau (p-tau181) in CSF associated with Alzheimer’s disease. Values are given as means ⁇ SEM.
  • FIGS.13A-13F show that development of a cell-permeable TAT-tagged KIBRA peptide derived from CT-KIBRA to restore synaptic plasticity and memory in AD and tauopathy-related dementia.
  • FIG.13A shows the amino acid sequence of the peptide being tested. This peptide is biotinylated and includes a TAT sequence to enable cell membrane permeability together with the sequence from within CT-KIBRA that is important for PKM ⁇ binding.
  • FIG.13B shows the mean intensity of the biotinylated peptide labeling in HEK293 cells was analyzed at the different concentrations of the peptide that were added to the cells.
  • FIG.13C shows the quantification of the TAT-KIBRA peptide labeling in dendritic spines of cultured rat neurons.
  • FIG.13D shows immunoblots of lysates from rat neuron culture treated with the TAT- KIBRA peptide to assess whether interacting proteins are pulled down with the TAT-KIBRA peptide. These results confirm that the TAT-KIBRA peptide binds to the KIBRA-interacting proteins, PKM ⁇ and PKC ⁇ , in rat neurons.
  • FIG.13E shows the quantification of immunoblot for PKM ⁇ from (FIG.13D) showing the dose-dependent binding of the TAT-KIBRA peptide to PKM ⁇ .
  • FIG.13F shows the quantification of GluA1-containing AMPA-type glutamate receptors (AMPARs) in postsynaptic spines of rat hippocampal cultured neurons with or without chemical LTP treatment.
  • AMPARs AMPA-type glutamate receptors
  • control neurons have increased postsynaptic AMPAR delivery into spines with chemical LTP induction compared to unstimulated control neurons.
  • the LTP expression is blocked in neurons with expression of a human tauKQ mutant that mimics pathogenic acetylated tau found in Alzheimer’s disease.
  • the TAT-KIBRA peptide treatment rescues the postsynaptic AMPAR delivery during LTP in neurons expressing pathogenic tau, but the TAT-KIBRA peptide has no effect on activity-induced AMPAR trafficking in control neurons.
  • FIGS.14A-14F show that TAT-KIBRA peptide improves memory and restores hippocampal synaptic plasticity in transgenic mice with pathogenic tau that causes Alheimer’s disease-related memory impairment.
  • FIG.14A shows data from an experiment in which non- transgenic (ntg) and tauKQ high mice were treated with either a vehicle control or the TAT- KIBRA peptide from an implanted osmotic pump with intracerebroventricular administration. The treated mice were tested in the object-context discrimination test of pattern separation.
  • FIGS.14B-14D show results from an experiment in which the ntg and tauKQ high mice treated with vehicle control and tauKQ high mice treated with TAT-KIBRA peptide were tested in the Morris water maze of spatial learning and memory.
  • FIG 14B During hidden platform training, the distance the mice travelled to the hidden platform decreased within five days of training, indicating spatial learning in all the mice. The mice were subjected to 24-hour and 120-hour probe trials to test spatial memory.
  • FIG.14C Representative swim paths of individual mice from each group within the maze during probe trials is plotted.
  • FIG.14D Quantification of the percent time spent in the target quadrant compared to the average of time in the other quadrants revealed that in the 120-hour probe test the impairment in long-term spatial memory in tauKQ high mice was rescued in those with TAT-KIBRA peptide treatment.
  • FIGS. 14E-14F show data from field recordings performed in the dentate gyrus of mouse brain slices that were acutely treated with either a TAT-scrambled control peptide or the TAT-KIBRA peptide.
  • FIG.14E The field excitatory postsynaptic potentials (fEPSP) were recorded in the dentate gyrus molecular layer in response to stimulation of the perforant pathway at increasing stimulus intensities.
  • FIG.14F Long-term potentiation (LTP) expression in tauKQ high mouse brain slices treated with the scrambled peptide was impaired, but the magnitude of LTP expression in tauKQ high mouse brain slices treated with TAT-KIBRA peptide was comparable to ntg mouse brain slices.
  • LTP Long-term potentiation
  • Nucleic acid refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In embodiments, “nucleic acid” does not include nucleosides.
  • polynucleotide oligonucleotide,” “oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides.
  • nucleoside refers, in the usual and customary sense, to a glycosylamine including a nucleobase and a five-carbon sugar (ribose or deoxyribose).
  • nucleosides include, cytidine, uridine, adenosine, guanosine, thymidine and inosine.
  • nucleotide refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof.
  • polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA.
  • nucleic acid e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof.
  • duplex in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched.
  • nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides.
  • the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.
  • Nucleic acids, including e.g., nucleic acids with a phosphothioate backbone can include one or more reactive moieties.
  • the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions.
  • the nucleic acid can include an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent, non-covalent or other interaction.
  • the terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non- naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides.
  • Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine.; and peptide nucleic acid backbones and linkages.
  • phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothio
  • nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Patent Nos.5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids.
  • LNA locked nucleic acids
  • Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip.
  • Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made.
  • the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.
  • Nucleic acids can include nonspecific sequences.
  • nonspecific sequence refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence.
  • a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.
  • a polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when the polynucleotide is RNA).
  • polynucleotide sequence is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself.
  • This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching.
  • Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and/or modified nucleotides.
  • complement refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides.
  • a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence.
  • the nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence.
  • Examples of complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence.
  • a further example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.
  • the complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing.
  • two sequences that are complementary to each other may have a specified percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region).
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ -carboxyglutamate, and O-phosphoserine.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an ⁇ carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.
  • non-naturally occurring amino acid refers to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.
  • a non-natural amino acid or a non-natural amino acid analog can replace a natural amino acid found in a KIBRA protein or a KIBRA peptide sequence described herein including embodiments thereof.
  • a non-natural amino acid or a non-natural amino acid analog can substitute a natural amino acid found in a KIBRA protein or a KIBRA peptide sequence described herein including embodiments thereof.
  • the non-natural amino acid or the non-natural amino acid analog is a ⁇ -amino acid.
  • ⁇ -amino acid refers to an amino acid where the stereogenic carbon alpha to the amino group has the ⁇ -configuration.
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.
  • polypeptide refers to a polymer of amino acid residues, wherein the polymer may In embodiments be conjugated to a moiety that does not consist of amino acids.
  • the terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.
  • a “fusion protein” refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.
  • amino acid or nucleotide base "position" is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N- terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion.
  • residues corresponding to a specific position in a protein e.g., KIBRA
  • identity and location of residues corresponding to specific positions of the protein are identified in other protein sequences aligning to the protein.
  • a selected residue in a selected protein corresponds to glutamic acid at position 138 when the selected residue occupies the same essential spatial or other structural relationship as a glutamic acid at position 138.
  • the position in the aligned selected protein aligning with glutamic acid 138 is the to correspond to glutamic acid 138.
  • a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the glutamic acid at position 138, and the overall structures compared.
  • an amino acid that occupies the same essential position as glutamic acid 138 in the structural model is the to correspond to the glutamic acid 138 residue.
  • nucleic acid sequences “conservatively modified variants” refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Because of the degeneracy of the genetic code, a number of nucleic acid sequences will encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations.
  • Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid.
  • each codon in a nucleic acid except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan
  • TGG which is ordinarily the only codon for tryptophan
  • the sequence of the “C- terminal KIBRA compound”, “C-terminal KIBRA peptide” and “CT-KIBRA” may be conservatively modified variant relative to a known C-terminal KIBRA peptide sequences, wherein the conservatively modified variant includes one or more conservative substitutions as described below.
  • conservatively modified variant includes one or more conservative substitutions as described below.
  • amino acid sequences one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid.
  • Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the disclosure.
  • the following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)).
  • nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site http://www.ncbi.nlm.nih.gov/BLAST/ or the like).
  • sequences are then said to be “substantially identical.”
  • This definition also refers to, or may be applied to, the compliment of a test sequence.
  • the definition also includes sequences that have deletions and/or additions, as well as those that have substitutions.
  • the preferred algorithms can account for gaps and the like.
  • identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.
  • Percentage of sequence identity is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.
  • a “comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of, e.g., a full length sequence or from 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.
  • Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman (1970) Adv. Appl.
  • Math.2:482c by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol.48:443, by the search for similarity method of Pearson and Lipman (1988) Proc. Nat’l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)).
  • An example of an algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res.25:3389-3402, and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively.
  • Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/).
  • This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence.
  • HSPs high scoring sequence pairs
  • T is referred to as the neighborhood word score threshold (Altschul et al., supra).
  • These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them.
  • the word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased.
  • Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always ⁇ 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score.
  • Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
  • the BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
  • the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc.
  • the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787).
  • One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance.
  • a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.
  • An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below.
  • a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions.
  • Antibodies are large, complex molecules (molecular weight of ⁇ 150,000 or about 1320 amino acids) with intricate internal structure.
  • a natural antibody molecule contains two identical pairs of polypeptide chains, each pair having one light chain and one heavy chain. Each light chain and heavy chain in turn consists of two regions: a variable (“V”) region, involved in binding the target antigen, and a constant (“C”) region that interacts with other components of the immune system.
  • V variable
  • C constant
  • the light and heavy chain variable regions (also referred to herein as light chain variable (VL) domain and heavy chain variable (VH) domain, respectively) come together in 3-dimensional space to form a variable region that binds the antigen (for example, a receptor on the surface of a cell).
  • VL light chain variable
  • VH heavy chain variable
  • two types of light chain are known: kappa chain (VK or V ⁇ ), encoded by the immunoglobulin kappa locus on chromosome 2, and the lambda chain (V ⁇ ), encoded by the immunoglobulin lambda locus on chromosome 22.
  • VK or V ⁇ kappa chain
  • V ⁇ the lambda chain
  • Within each light or heavy chain variable region there are three short segments (averaging 10 amino acids in length) called the complementarity determining regions (“CDRs”).
  • an “antibody variant” as provided herein refers to a polypeptide capable of binding to an antigen and including one or more structural domains (e.g., light chain variable domain, heavy chain variable domain) of an antibody or fragment thereof.
  • Non-limiting examples of antibody variants include single-domain antibodies or nanobodies, monospecific Fab2, bispecific Fab2, trispecific Fab3, monovalent IgGs, scFv, bispecific antibodies, bispecific diabodies, trispecific triabodies, scFv-Fc, minibodies, IgNAR, V-NAR, hcIgG, VhH, or peptibodies.
  • a “peptibody” as provided herein refers to a peptide moiety attached (through a covalent or non-covalent linker) to the Fc domain of an antibody.
  • Further non-limiting examples of antibody variants known in the art include antibodies produced by cartilaginous fish or camelids.
  • CDR L1 refers to the complementarity determining regions (CDR) 1, 2, and 3 of the variable light (L) chain of an antibody.
  • variable light chain provided herein includes in to C-terminal direction a CDR L1, a CDR L2 and a CDR L3.
  • CDR H1", CDR H2" and CDR H3 refer to the complementarity determining regions (CDR) 1, 2, and 3 of the variable heavy (H) chain of an antibody.
  • the variable heavy chain provided herein includes in N-terminal to C-terminal direction a CDR H1, a CDR H2 and a CDR H3.
  • FR L1 FR L2
  • FR L3 FR L4
  • FR L4 the terms “FR H1”, “FR H2”, “FR H3” and “FR H4" as provided herein are used according to their common meaning in the art and refer to the framework regions (FR) 1, 2, 3 and 4 of the variable heavy (H) chain of an antibody.
  • variable heavy chain includes in N-terminal to C-terminal direction a FR H1, a FR H2, a FR H3 and a FR H4.
  • An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • variable light chain (VL), variable light chain (VL) domain or light chain variable region and variable heavy chain (VH), variable heavy chain (VH) domain or heavy chain variable region refer to these light and heavy chain regions, respectively.
  • variable light chain (VL), variable light chain (VL) domain and light chain variable region as referred to herein may be used interchangeably.
  • variable heavy chain (VH), variable heavy chain (VH) domain and heavy chain variable region as referred to herein may be used interchangeably.
  • the Fc i.e. fragment crystallizable region
  • the Fc region By binding to specific proteins, the Fc region ensures that each antibody generates an appropriate immune response for a given antigen.
  • the Fc region also binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins.
  • the term "antibody” is used according to its commonly known meaning in the art. Antibodies exist, e.g., as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to V H -C H1 by a disulfide bond.
  • the F(ab)' 2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer into an Fab' monomer.
  • the Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed.1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology.
  • antibody also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554 (1990)).
  • antibody as referred to herein further includes antibody variants such as single domain antibodies.
  • an antibody includes a single monomeric variable antibody domain.
  • the antibody includes a variable light chain (VL) domain or a variable heavy chain (VH) domain.
  • the antibody is a variable light chain (VL) domain or a variable heavy chain (VH) domain.
  • VL variable light chain
  • VH variable heavy chain
  • a variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein.
  • solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity).
  • a "ligand” refers to an agent, e.g., a polypeptide or other molecule, capable of binding to a receptor or antibody, antibody variant, antibody region or fragment thereof.
  • the named protein includes any of the protein’s naturally occurring forms, variants or homologs that maintain the protein transcription factor activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to the native protein).
  • variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring form.
  • the protein is the protein as identified by its NCBI sequence reference.
  • the protein is the protein as identified by its NCBI sequence reference, homolog or functional fragment thereof.
  • the term “KIBRA compound” as used herein refers to a compound comprising a KIBRA protein or KIBRA peptide provided herein including embodiments thereof.
  • the KIBRA compound comprises a KIBRA peptide attached to an amino acid sequence that is not a KIBRA peptide or a sequence found within a KIBRA peptide sequence.
  • the KIBRA compound does not include, and is not attached to, any additional amino acid sequence found within a KIBRA protein or any additional amino acid sequence found within a KIBRA peptide sequence.
  • the KIBRA compound does not comprise an N-terminal KIBRA protein or an N-terminal KIBRA peptide as provided herein including embodiments thereof.
  • the terms "KIBRA protein”, “KIBRA peptide” and “KIBRA” as used herein include any of the recombinant or naturally-occurring forms of the kidney and brain expressed protein, also known as WW domain-containing protiein 1 (WWC1), or variants or homologs thereof that maintain KIBRA activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to KIBRA (e.g. the UniProt reference number Q8IX03)).
  • the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100 continuous amino acid portion) compared to a naturally occurring KIBRA protein (e.g. UniProt reference number Q8IX03).
  • a naturally occurring KIBRA protein e.g. UniProt reference number Q8IX03
  • the KIBRA protein is substantially identical to the protein identified by the UniProt reference number Q8IX03 or a variant or homolog having substantial identity thereto.
  • C-terminal KIBRA compound refers to a compound comprising a C-terminal KIBRA protein or C-terminal KIBRA peptide as provided herein including embodiments thereof.
  • the C-terminal KIBRA compound does not comprise an N-terminal KIBRA protein or an N-terminal KIBRA peptide as provided herein including embodiments thereof.
  • the C-terminal KIBRA compound comprises a KIBRA peptide attached to an amino acid sequence that is not a KIBRA peptide or a sequence found within a KIBRA peptide sequence.
  • the C-terminal KIBRA compound does not include, and is not attached to, any additional amino acid sequence found within a KIBRA protein or any additional amino acid sequence found within a KIBRA peptide sequence.
  • the C-terminal KIBRA compound comprises a cell-penetrating peptide or a blood-brain barrier-penetrating peptide.
  • the C-terminal KIBRA compound comprises a cell-penetrating peptide.
  • the C-terminal KIBRA compound comprises a blood-brain barrier-penetrating peptide.
  • C-terminal KIBRA protein refers a peptide that includes a C-terminal amino acid sequence of the KIBRA protein (e.g. the UniProt reference number Q8IX03) and is less than 800 (e.g.700, 600, 500, 400, 300, 200, 100, 50, 40, 20, or 10) amino acids in length.
  • the C- terminal KIBRA peptide comprises a C-terminal amino acid sequence of the KIBRA protein attached to an amino acid sequence that is not a KIBRA peptide or a sequence found within a KIBRA peptide sequence.
  • the C-terminal KIBRA peptide does not include, and is not attached to, any additional amino acid found within a KIBRA protein or any additional amino acid sequence found within a KIBRA peptide sequence.
  • the C-terminal KIBRA protein does not comprise an N-terminal KIBRA protein or an N-terminal KIBRA peptide as provided herein including embodiments thereof.
  • the “C-terminal amino acid sequence” is an amino acid sequence that includes at least 10 contiguous amino acids of the KIBRA protein within 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 25 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 10 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the CT-KIBRA protein sequence includes SEQ ID NO:1.
  • the CT-KIBRA protein sequence includes SEQ ID NO:2.
  • the CT-KIBRA protein sequence includes SEQ ID NO:3.
  • N-terminal KIBRA protein refers a peptide that includes an N-terminal amino acid sequence of the KIBRA protein (e.g., the UniProt reference number Q8IX03) and is less than 86 (e.g., 80, 70, 60, 50, 40, 30, 20, or 10) amino acids in length.
  • the N-terminal KIBRA peptide comprises an N-terminal amino acid sequence of the KIBRA protein attached to an amino acid sequence that is not a KIBRA peptide or a sequence found within a KIBRA peptide sequence.
  • the N-terminal KIBRA peptide does not include, and is not attached to, any additional amino acid found within a KIBRA protein or any additional amino acid sequence found within a KIBRA peptide sequence.
  • the N-terminal KIBRA protein does not comprise a C-terminal KIBRA protein or a C-terminal KIBRA peptide as provided herein including embodiments thereof.
  • the “N-terminal amino acid sequence” is an amino acid sequence that includes at least 10 contiguous amino acids of the KIBRA protein within 86 amino acids of the N-terminus of the KIBRA protein (e.g., the UniProt reference number Q8IX03).
  • the N-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 80 amino acids of the N-terminus of the KIBRA protein (e.g., the UniProt reference number Q8IX03). In embodiments, the N-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 70 amino acids of the N-terminus of the KIBRA protein (e.g., the UniProt reference number Q8IX03).
  • the N- terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 60 amino acids of the N-terminus of the KIBRA protein (e.g., the UniProt reference number Q8IX03). In embodiments, the N-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 50 amino acids of the N-terminus of the KIBRA protein (e.g., the UniProt reference number Q8IX03).
  • the N-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 40 amino acids of the N-terminus of the KIBRA protein (e.g., the UniProt reference number Q8IX03). In embodiments, the N-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 30 amino acids of the N-terminus of the KIBRA protein (e.g., the UniProt reference number Q8IX03).
  • the N-terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 20 amino acids of the N-terminus of the KIBRA protein (e.g., the UniProt reference number Q8IX03).
  • the N- terminal amino acid sequence is an amino acid sequence that includes at least 10 continuous amino acids of the KIBRA protein within 10 amino acids of the N-terminus of the KIBRA protein (e.g., the UniProt reference number Q8IX03).
  • the NT-KIBRA protein sequence does not include SEQ ID NO:1.
  • the NT-KIBRA protein sequence does not include SEQ ID NO:2.
  • the NT-KIBRA protein sequence does not include SEQ ID NO:3.
  • tau and tau protein as used herein include any of the recombinant or naturally-occurring forms of the tubulin associated unit, or variants or homologs thereof that maintain tau activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to tau (e.g. UniProt reference number P10636)).
  • the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150, 200 continuous amino acid portion) compared to a naturally occurring tau protein (e.g.
  • the tau protein is substantially identical to the protein identified by the UniProt reference number P10636 or a variant or homolog having substantial identity thereto.
  • the term “cell-penetrating peptides” as used herein refers to short peptides that are able to pass through tissue and cell membranes. In embodiments, cell-penetrating peptides are used to transport biologically active conjugates into tissues or cells. In embodiments, the biologically active conjugates are peptides. In embodiments, the biologically active conjugate is a KIBRA peptide. In further embodiments, the KIBRA peptide is a CT-KIBRA peptide.
  • the cell-penetrating peptide includes, but is not limited to, a TAT amino acid sequence, a penetratin amino acid sequence, an oligoarginine amino acid sequence, a xentry amino acid sequence, a transportan amino acid sequence, a cyclic-TAT amino acid sequence, a cyclic penetratin amino acid sequence, a cyclic oligoarginine amino acid sequence, a cyclic xentry amino acid sequence, or a cyclic transportan amino acid sequence.
  • the cell-penetrating peptide includes the amino acid sequence of SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25.
  • blood-brain barrier-penetrating peptides or “BBB-penetrating peptides” as used herein refer to polypeptides that are able to pass through the blood-brain barrier.
  • the BBB-penetrating peptides are used to transport biologically active conjugates into the brain.
  • the biologically active conjugate is a KIBRA peptide.
  • the KIBRA peptide is a CT-KIBRA peptide.
  • Blood-brain barrier-penetrating peptides are well known in the art (Kariolis et al., Sci Transl Med, 2020, 12(545): eaay1359).
  • the blood-brain barrier-penetrating peptide includes, but is not limited to, an Fc fragment blood-brain barrier transport vehicle.
  • the term "gene” means the segment of DNA involved in producing a protein; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons). The leader, the trailer as well as the introns include regulatory elements that are necessary during the transcription and the translation of a gene. Further, a "protein gene product” is a protein expressed from a particular gene.
  • plasmid refers to a nucleic acid molecule that encodes for genes and/or regulatory elements necessary for the expression of genes. Expression of a gene from a plasmid can occur in cis or in trans. If a gene is expressed in cis, the gene and the regulatory elements are encoded by the same plasmid. Expression in trans refers to the instance where the gene and the regulatory elements are encoded by separate plasmids.
  • transfection transduction
  • transfecting or transducing
  • Nucleic acids are introduced to a cell using non-viral or viral-based methods.
  • the nucleic acid molecules may be gene sequences encoding complete proteins or functional portions thereof.
  • Non-viral methods of transfection include any appropriate transfection method that does not use viral DNA or viral particles as a delivery system to introduce the nucleic acid molecule into the cell.
  • Exemplary non-viral transfection methods include calcium phosphate transfection, liposomal transfection, nucleofection, sonoporation, transfection through heat shock, magnetifection and electroporation.
  • the nucleic acid molecules are introduced into a cell using electroporation following standard procedures well known in the art.
  • electroporation any useful viral vector may be used in the methods described herein.
  • viral vectors examples include, but are not limited to retroviral, adenoviral, lentiviral and adeno-associated viral vectors.
  • the nucleic acid molecules are introduced into a cell using a retroviral vector following standard procedures well known in the art.
  • the terms ′′transfection′′ or ′′transduction′′ also refer to introducing proteins into a cell from the external environment. Typically, transduction or transfection of a protein relies on attachment of a peptide or protein capable of crossing the cell membrane to the protein of interest. See, e.g., Ford et al. (2001) Gene Therapy 8:1-4 and Prochiantz (2007) Nat. Methods 4:119-20.
  • a “label” or a “detectable moiety” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means.
  • useful labels include 32P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide.
  • the agent may be reacted with another long-tailed reagent having a long tail with one or more chelating groups attached to the long tail for binding to these ions.
  • the long tail may be a polymer such as a polylysine, polysaccharide, or other derivatized or derivatizable chain having pendant groups to which the metals or ions may be added for binding.
  • chelating groups examples include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), DOTA, NOTA, NETA, TETA, porphyrins, polyamines, crown ethers, bis-thiosemicarbazones, polyoximes, and like groups.
  • EDTA ethylenediaminetetraacetic acid
  • DTPA diethylenetriaminepentaacetic acid
  • DOTA DOTA
  • NOTA NETA
  • TETA NETA
  • porphyrins polyamines
  • crown ethers bis-thiosemicarbazones
  • polyoximes and like groups.
  • the chelate is normally linked to the PSMA antibody or functional antibody fragment by a group, which enables the formation of a bond to the molecule with minimal loss of immunoreactivity and minimal aggregation and/or internal cross-linking.
  • chelates when complexed with non-radioactive metals, such as manganese, iron and gadolinium are useful for MRI, when used along with the antibodies and carriers described herein.
  • Macrocyclic chelates such as NOTA, DOTA, and TETA are of use with a variety of metals and radiometals including, but not limited to, radionuclides of gallium, yttrium and copper, respectively.
  • Other ring-type chelates such as macrocyclic polyethers, which are of interest for stably binding nuclides, such as 223 Ra for RAIT may be used.
  • chelating moieties may be used to attach a PET imaging agent, such as an Al- 18 F complex, to a targeting molecule for use in PET analysis.
  • a PET imaging agent such as an Al- 18 F complex
  • a targeting molecule for use in PET analysis.
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. antibodies and antigens) to become sufficiently proximal to react, interact, or physically touch. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.
  • the term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be, for example, a pharmaceutical composition as provided herein and a cell. In embodiments contacting includes, for example, allowing a pharmaceutical composition as described herein to interact with a cell.
  • a "cell” as used herein refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring.
  • Cells may include prokaryotic and eukaryotic cells.
  • Prokaryotic cells include but are not limited to bacteria.
  • Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells.
  • recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all.
  • Transgenic cells and plants are those that express a heterologous gene or coding sequence, typically as a result of recombinant methods.
  • isolated when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution.
  • nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature.
  • the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source.
  • heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).
  • exogenous refers to a molecule or substance (e.g., a compound, nucleic acid or protein) that originates from outside a given cell or organism.
  • an "exogenous promoter” as referred to herein is a promoter that does not originate from the cell or organism it is expressed by.
  • endogenous or endogenous promoter refers to a molecule or substance that is native to, or originates within, a given cell or organism.
  • the term "expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post- translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).
  • Biological sample or “sample” refer to materials obtained from or derived from a subject or patient. A biological sample includes sections of tissues such as biopsy and autopsy samples, and frozen sections taken for histological purposes.
  • Such samples include bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells) stool, urine, synovial fluid, joint tissue, synovial tissue, synoviocytes, fibroblast-like synoviocytes, macrophage-like synoviocytes, immune cells, hematopoietic cells, fibroblasts, macrophages, T cells, etc.
  • bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells) stool, urine, synovial fluid, joint tissue, synovial tissue, synoviocytes, fibroblast-like synoviocytes, macrophage-like synoviocytes, immune cells, hematopoietic cells, fibroblasts
  • a biological sample is typically obtained from a eukaryotic organism, such as a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish.
  • a “control” or “standard control” refers to a sample, measurement, or value that serves as a reference, usually a known reference, for comparison to a test sample, measurement, or value.
  • a test sample can be taken from a patient suspected of having a given disease (e.g. Alzheimer’s disease) and compared to a known normal (non-diseased) individual (e.g.
  • a standard control can also represent an average measurement or value gathered from a population of similar individuals (e.g. standard control subjects) that do not have a given disease (i.e. standard control population), e.g., healthy individuals with a similar medical background, same age, weight, etc.
  • a standard control value can also be obtained from the same individual, e.g. from an earlier-obtained sample from the patient prior to disease onset.
  • a control can be devised to compare therapeutic benefit based on pharmacological data (e.g., half-life) or therapeutic measures (e.g., comparison of side effects). Controls are also valuable for determining the significance of data.
  • Standard controls can be designed for assessment of any number of parameters (e.g. RNA levels, protein levels, specific cell types, specific bodily fluids, specific tissues, etc). [0080] One of skill in the art will understand which standard controls are most appropriate in a given situation and be able to analyze data based on comparisons to standard control values. Standard controls are also valuable for determining the significance (e.g. statistical significance) of data. For example, if values for a given parameter are widely variant in standard controls, variation in test samples will not be considered as significant.
  • “Patient” or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a composition or pharmaceutical composition as provided herein.
  • Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
  • a patient is human.
  • the terms “disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.
  • the disease may be a tau-associated memory deficit disorder.
  • the tau-associated memory deficit disorder may include Alzheimer’s disease, progressive supranuclear palsy, Pick’s disease, corticobasal degeneration, chronic traumatic encephalopathy, or Frontotemporal lobar dementia- tau (FTLD-tau).
  • the condition may be aging-associated cognitive decline.
  • the aging-associated cognitive decline occur in the absence of tau- associated neurodegeneration.
  • the term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease e.g. a protein associated disease, a memory deficit disorder associated with tau activity, memory deficits associated with tau pathogy, tau-associated disease, tau-associated degerenation
  • a disease e.g. a protein associated disease, a memory deficit disorder associated with tau activity, memory deficits associated with tau pathogy, tau-associated disease, tau-associated degerenation
  • memory deficit disorder is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function.
  • a memory deficit dorder associated with tau activity or function or a tau-associated disease e.g., memory deficit disorder
  • the term “memory deficit disorder”, “memory deficit” and “memory disorder” as used herein refers to condition characterized by an impairment of memory as manifested by a reduced ability to remember things such as dates and names, and increased forgetfulness.
  • the memory deficit disorder is associated with aberrant tau expression and activity or a tauopathy.
  • the memory deficit disorder is a tau-associated memory deficit disorder.
  • tauopathy refers to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain.
  • the tangles are formed by hyperphosphorylation of tau, causing the protein to dissociate from microtubules and form insoluble aggregates.
  • neurodegeneration refers to a disease or condition which is characterized by a slow and progressive loss of neuronal cells in specified regions of the brain.
  • the neurodegerneation is tau-associated.
  • cognitive decline refers to the gradual loss of cognitive or thinking abilities (e.g. learning, remembering, attention, reasoning) in a subject.
  • the cognitive decline is aging-associated.
  • the cognitive decline is mild.
  • the cognitive decline occurs in the absence of tau-associated neurodegeneration.
  • the cognitive decline is associated with a cognitive disorder. In embodiments, the cognitive decline is tau-associated.
  • signaling pathway refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components.
  • aberrant refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples.
  • Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non- disease-associated amount (e.g. by using a method as described herein), results in reduction of the disease or one or more disease symptoms.
  • “treating” or “treatment of” a condition, disease or disorder or symptoms associated with a condition, disease or disorder refers to an approach for obtaining beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of condition, disorder or disease, stabilization of the state of condition, disorder or disease, prevention of development of condition, disorder or disease, prevention of spread of condition, disorder or disease, delay or slowing of condition, disorder or disease progression, delay or slowing of condition, disorder or disease onset, amelioration or palliation of the condition, disorder or disease state, and remission, whether partial or total. “Treating” can also mean prolonging survival of a subject beyond that expected in the absence of treatment.
  • Treating can also mean inhibiting the progression of the condition, disorder or disease, slowing the progression of the condition, disorder or disease temporarily, although in some instances, it involves halting the progression of the condition, disorder or disease permanently.
  • treatment, treat, or treating refers to a method of reducing the effects of one or more symptoms of a disease or condition characterized by expression of the protease or symptom of the disease or condition characterized by expression of the protease.
  • treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition.
  • a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control.
  • the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels.
  • treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition.
  • references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination.
  • dose refers to the amount of active ingredient given to an individual at each administration.
  • the dose will vary depending on a number of factors, including the range of normal doses for a given therapy, frequency of administration; size and tolerance of the individual; severity of the condition; risk of side effects; and the route of administration.
  • dose form refers to the particular format of the pharmaceutical or pharmaceutical composition, and depends on the route of administration.
  • a dosage form can be in a liquid form for nebulization, e.g., for inhalants, in a tablet or liquid, e.g., for oral delivery, or a saline solution, e.g., for injection.
  • a saline solution e.g., for injection.
  • a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%.
  • Therapeutic efficacy can also be expressed as “-fold” increase or decrease.
  • a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a standard control.
  • a therapeutically effective dose or amount may ameliorate one or more symptoms of a disease.
  • a therapeutically effective dose or amount may prevent or delay the onset of a disease or one or more symptoms of a disease when the effect for which it is being administered is to treat a person who is at risk of developing the disease.
  • administering means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy.
  • the compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • the compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat.
  • compositions of the present invention can also be delivered as microspheres for slow release in the body.
  • microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed.7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res.12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm.
  • the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis.
  • liposomes particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.13:293-306, 1996; Chonn, Curr.
  • compositions of the present invention can also be delivered as nanoparticles.
  • pharmaceutically acceptable is used synonymously with “physiologically acceptable” and “pharmacologically acceptable”.
  • a pharmaceutical composition will generally comprise agents for buffering and preservation in storage, and can include buffers and carriers for appropriate delivery, depending on the route of administration.
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents
  • pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • preparation is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • a carrier which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • the pharmaceutical preparation is optionally in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the unit dosage form can be of a frozen dispersion.
  • the terms “1-ethyl-3-(-3-dimethyoaminopropyl) carbodiimide”, “EDC”, “EDAC” and “EDCI” as used herein refer to a water-soluble carbodiimide usually handled as the hydrochloride. It is generally used as a carboxyl activating agent for the coupling of primary amines to yield amide bonds. Additionally, EDC can also be used to activate phosphate groups in order to form phosphomonoesters and phosphodiesters.
  • carbodiimide Common uses for this carbodiimide include peptide synthesis, protein crosslinking to nucleic acids, but also in the preparation of immunoconjugates. EDC is often used in combination with N-hydroxysuccinimide (NHS) for the immobilisation of large biomolecules. Recent work has also used EDC to assess the structure state of uracil nucleobases in RNA. [0101]
  • N-hydroxysulfosuccinimide”, “sulfo-NHS” and “NHS” refer to a compound that enables control and modification of carbodiimide crosslinking reactions involving activation of carboxylates (—COOH) for conjugation with primary amines (—NH2).
  • Derivatives can be synthesized by mixing the NHS with a carboxyl-containing molecule and a dehydrating agent such as the carbodiimide EDC.
  • the method is the basis for generating many types of protein labeling reagents, including amine-reactive fluorescent dyes, biotin affinity tags and pegylation compounds.
  • a memory deficit disorder e.g. tau-associated memory deficit disorder
  • a method of treating a tau-associated memory deficit disorder in a subject in need thereof including administering to the subject a therapeutically effective amount of a C-terminal KIBRA compound.
  • the tau-associated memory deficit disorder is Alzheimer’s disease, progressive supranuclear palsy, Pick’s disease, corticobasal degeneration, chronic traumatic encephalopathy, or Frontotemporal lobar dementia-tau (FTLD-tau).
  • the C-terminal KIBRA compound is a peptide.
  • the C-terminal KIBRA compound includes a C-terminal KIBRA peptide.
  • the C- terminal KIBRA peptide is between about 700 and about 800 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 710 and about 800 amino acids in length.
  • the C-terminal KIBRA peptide is between about 720 and about 800 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 730 and about 800 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 740 and about 800 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 750 and about 800 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 760 and about 800 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 770 and about 800 amino acids in length.
  • the C-terminal KIBRA peptide is between about 780 and about 800 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 790 and about 800 amino acids in length. [0106] In embodiments, the C-terminal KIBRA peptide is between about 700 and about 790 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 700 and about 780 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 700 and about 770 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 700 and about 760 amino acids in length.
  • the C-terminal KIBRA peptide is between about 700 and about 750 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 700 and about 740 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 700 and about 730 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 700 and about 720 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 700 and about 710 amino acids in length. [0107] In embodiments, the C-terminal KIBRA peptide is between about 600 and about 700 amino acids in length.
  • the C-terminal KIBRA peptide is between about 610 and about 700 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 620 and about 700 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 630 and about 700 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 640 and about 700 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 650 and about 700 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 660 and about 700 amino acids in length.
  • the C-terminal KIBRA peptide is between about 670 and about 700 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 680 and about 700 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 690 and about 700 amino acids in length. [0108] In embodiments, the C-terminal KIBRA peptide is between about 600 and about 690 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 600 and about 680 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 600 and about 670 amino acids in length.
  • the C-terminal KIBRA peptide is between about 600 and about 660 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 600 and about 650 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 600 and about 640 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 600 and about 630 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 600 and about 620 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 600 and about 610 amino acids in length.
  • the C-terminal KIBRA peptide is between about 500 and about 600 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 510 and about 600 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 520 and about 600 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 530 and about 600 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 540 and about 600 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 550 and about 600 amino acids in length.
  • the C-terminal KIBRA peptide is between about 560 and about 600 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 570 and about 600 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 580 and about 600 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 590 and about 600 amino acids in length. [0110] In embodiments, the C-terminal KIBRA peptide is between about 500 and about 590 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 500 and about 580 amino acids in length.
  • the C-terminal KIBRA peptide is between about 500 and about 570 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 500 and about 560 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 500 and about 550 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 500 and about 540 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 500 and about 530 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 500 and about 520 amino acids in length.
  • the C-terminal KIBRA peptide is between about 500 and about 510 amino acids in length. [0111] In embodiments, the C-terminal KIBRA peptide is between about 400 and about 500 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 410 and about 500 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 420 and about 500 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 430 and about 500 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 440 and about 500 amino acids in length.
  • the C-terminal KIBRA peptide is between about 450 and about 500 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 460 and about 500 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 470 and about 500 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 480 and about 500 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 490 and about 500 amino acids in length. [0112] In embodiments, the C-terminal KIBRA peptide is between about 400 and about 490 amino acids in length.
  • the C-terminal KIBRA peptide is between about 400 and about 480 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 400 and about 470 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 400 and about 460 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 400 and about 450 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 400 and about 440 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 400 and about 430 amino acids in length.
  • the C-terminal KIBRA peptide is between about 400 and about 420 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 400 and about 410 amino acids in length. [0113] In embodiments, the C-terminal KIBRA peptide is between about 300 and about 400 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 310 and about 400 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 320 and about 400 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 330 and about 400 amino acids in length.
  • the C-terminal KIBRA peptide is between about 340 and about 400 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 350 and about 400 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 360 and about 400 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 370 and about 400 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 380 and about 400 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 390 and about 400 amino acids in length.
  • the C-terminal KIBRA peptide is between about 300 and about 390 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 300 and about 380 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 300 and about 370 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 300 and about 360 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 300 and about 350 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 300 and about 340 amino acids in length.
  • the C-terminal KIBRA peptide is between about 300 and about 330 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 300 and about 320 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 300 and about 310 amino acids in length. [0115] In embodiments, the C-terminal KIBRA peptide is between about 200 and about 300 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 210 and about 300 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 220 and about 300 amino acids in length.
  • the C-terminal KIBRA peptide is between about 230 and about 300 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 240 and about 300 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 250 and about 300 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 260 and about 300 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 270 and about 300 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 280 and about 300 amino acids in length.
  • the C-terminal KIBRA peptide is between about 290 and about 300 amino acids in length. [0116] In embodiments, the C-terminal KIBRA peptide is between about 200 and about 290 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 200 and about 280 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 200 and about 270 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 200 and about 260 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 200 and about 250 amino acids in length.
  • the C-terminal KIBRA peptide is between about 200 and about 240 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 200 and about 230 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 200 and about 220 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 200 and about 210 amino acids in length. [0117] In embodiments, the C-terminal KIBRA peptide is between about 100 and about 200 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 110 and about 200 amino acids in length.
  • the C-terminal KIBRA peptide is between about 120 and about 200 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 130 and about 200 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 140 and about 200 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 150 and about 200 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 160 and about 200 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 170 and about 200 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 180 and about 200 amino acids in length.
  • the C-terminal KIBRA peptide is between about 190 and about 200 amino acids in length. [0118] In embodiments, the C-terminal KIBRA peptide is between about 100 and about 190 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 100 and about 180 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 100 and about 170 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 100 and about 160 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 100 and about 150 amino acids in length.
  • the C-terminal KIBRA peptide is between about 100 and about 140 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 100 and about 130 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 100 and about 120 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 100 and about 110 amino acids in length. [0119] In embodiments, the C-terminal KIBRA peptide is between about 50 and about 100 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 60 and about 100 amino acids in length.
  • the C-terminal KIBRA peptide is between about 70 and about 100 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 80 and about 100 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 90 and about 100 amino acids in length. [0120] In embodiments, the C-terminal KIBRA peptide is between about 50 and about 90 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 50 and about 80 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 50 and about 70 amino acids in length.
  • the C-terminal KIBRA peptide is between about 50 and about 60 amino acids in length. [0121] In embodiments, the C-terminal KIBRA peptide is between about 40 and about 50 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 41 and about 50 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 42 and about 50 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 43 and about 50 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 44 and about 50 amino acids in length.
  • the C-terminal KIBRA peptide is between about 45 and about 50 amino acids in length. In embodiments, the C- terminal KIBRA peptide is between about 46 and about 50 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 47 and about 50 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 48 and about 50 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 49 and about 50 amino acids in length. [0122] In embodiments, the C-terminal KIBRA peptide is between about 40 and about 49 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 40 and about 48 amino acids in length.
  • the C-terminal KIBRA peptide is between about 40 and about 47 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 40 and about 46 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 40 and about 45 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 40 and about 44 amino acids in length. In embodiments, the C- terminal KIBRA peptide is between about 40 and about 43 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 40 and about 42 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 40 and about 41 amino acids in length.
  • the C-terminal KIBRA peptide is between about 20 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 21 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 22 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 23 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 24 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 25 and about 40 amino acids in length. In embodiments, the C- terminal KIBRA peptide is between about 26 and about 40 amino acids in length.
  • the C-terminal KIBRA peptide is between about 27 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 28 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 29 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 30 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 31 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 32 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 33 and about 40 amino acids in length.
  • the C-terminal KIBRA peptide is between about 34 and about 40 amino acids in length. In embodiments, the C- terminal KIBRA peptide is between about 35 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 36 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 37 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 38 and about 40 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 39 and about 40 amino acids in length. [0124] In embodiments, the C-terminal KIBRA peptide is between about 20 and about 39 amino acids in length.
  • the C-terminal KIBRA peptide is between about 20 and about 38 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 37 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 36 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 35 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 34 amino acids in length. In embodiments, the C- terminal KIBRA peptide is between about 20 and about 33 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 32 amino acids in length.
  • the C-terminal KIBRA peptide is between about 20 and about 31 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 30 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 29 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 28 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 27 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 26 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 25 amino acids in length.
  • the C- terminal KIBRA peptide is between about 20 and about 24 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 23 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 22 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 20 and about 21 amino acids in length. [0125] In embodiments, the C-terminal KIBRA peptide is between about 10 and about 20 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 11 and about 20 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 12 and about 20 amino acids in length.
  • the C-terminal KIBRA peptide is between about 13 and about 20 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 14 and about 20 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 15 and about 20 amino acids in length. In embodiments, the C- terminal KIBRA peptide is between about 16 and about 20 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 17 and about 20 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 18 and about 20 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 19 and about 20 amino acids in length.
  • the C-terminal KIBRA peptide is between about 10 and about 19 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 10 and about 18 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 10 and about 17 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 10 and about 16 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 10 and about 15 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 10 and about 14 amino acids in length. In embodiments, the C- terminal KIBRA peptide is between about 10 and about 13 amino acids in length.
  • the C-terminal KIBRA peptide is between about 10 and about 12 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 10 and about 11 amino acids in length. [0127] In embodiments, the C-terminal KIBRA peptide is between about 5 and about 10 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 6 and about 10 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 7 and about 10 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 8 and about 10 amino acids in length.
  • the C-terminal KIBRA peptide is between about 9 and about 10 amino acids in length. [0128] In embodiments, the C-terminal KIBRA peptide is between about 5 and about 9 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 5 and about 8 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 5 and about 7 amino acids in length. In embodiments, the C-terminal KIBRA peptide is between about 5 and about 6 amino acids in length.
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 50 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C- terminal KIBRA peptide has at least 85% amino acid sequence identity across a 100 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 200 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 300 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 400 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 500 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 600 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 700 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 800 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 50 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C- terminal KIBRA peptide has at least 90% amino acid sequence identity across a 100 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 200 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 300 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 400 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 500 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 600 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 700 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 800 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 50 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C- terminal KIBRA peptide has at least 95% amino acid sequence identity across a 100 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 200 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 600 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 700 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 800 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 50 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C- terminal KIBRA peptide has at least 99% amino acid sequence identity across a 100 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 200 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 300 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 400 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 500 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 600 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 700 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 800 continuous amino acid portion of the sequence compared to a naturally occurring KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 500 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 400 continous amino acid sequence portion within at least 500 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 400 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 400 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0135] In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 300 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 200 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 100 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0139] In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 25 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 25 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0140] In embodiments, the C-terminal KIBRA peptide has at least 85% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 10 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 500 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 400 continous amino acid sequence portion within at least 500 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 400 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 400 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0143] In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 300 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0144] In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 200 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 100 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0147] In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 25 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 25 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0148] In embodiments, the C-terminal KIBRA peptide has at least 90% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 10 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 500 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 400 continous amino acid sequence portion within at least 500 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 400 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 400 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 300 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0152] In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 200 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 100 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0155] In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 25 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 25 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0156] In embodiments, the C-terminal KIBRA peptide has at least 95% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 10 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 500 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 400 continous amino acid sequence portion within at least 500 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 500 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 400 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 400 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 400 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0159] In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 300 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 300 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 300 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0160] In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 200 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 200 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 200 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 100 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 100 amino acids of the C- terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 100 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 50 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 50 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0163] In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 25 continous amino acid sequence portion within at least 25 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03).
  • the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 25 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0164] In embodiments, the C-terminal KIBRA peptide has at least 99% amino acid sequence identity across a 10 continous amino acid sequence portion within at least 10 amino acids of the C-terminus of the KIBRA protein (e.g. the UniProt reference number Q8IX03). [0165] In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:1. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:2. In embodiments, the C- terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:3. In embodiments, the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3. In embodiments, the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:1. In embodiments, the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:2. In embodiments, the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:3.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:4. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:5. In embodiments, the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5. In embodiments, the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:4. In embodiments, the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:5.
  • the C-terminal KIBRA compound includes a cell-penetrating peptide or a blood-brain barrier-penetrating peptide. In embodiments, the C-terminal KIBRA compound includes a cell-penetrating peptide. In embodiments, the C-terminal KIBRA compound includes a blood-brain barrier-penetrating peptide.
  • the C-terminal KIBRA compound includes a TAT amino acid sequence, a penetratin amino acid sequence, an oligoarginine amino acid sequence, a xentry amino acid sequence, a transportan amino acid sequence, a cyclic-TAT amino acid sequence, a cyclic penetratin amino acid sequence, a cyclic oligoarginine amino acid sequence, a cyclic xentry amino acid sequence, a cyclic transportan amino acid sequence, a hydrocarbon stapling sequence, a glycine flexible linker, or a biotin amino acid sequence.
  • the C-terminal KIBRA compound includes a TAT amino acid sequence.
  • the C-terminal KIBRA compound includes a penetratin amino acid sequence. In embodiments, the C-terminal KIBRA compound includes a oligoarginine amino acid sequence. In embodiments, the C-terminal KIBRA compound includes a xentry amino acid sequence.In embodiments, the C-terminal KIBRA compound includes a transportan amino acid sequence. In embodiments, the C-terminal KIBRA compound includes a cyclic-TAT amino acid sequence. In embodiments, the C-terminal KIBRA compound includes a cyclic penetratin amino acid sequence. In embodiments, the C-terminal KIBRA compound includes a cyclic oligoarginine amino acid sequence.
  • the C-terminal KIBRA compound includes a cyclic xentry amino acid sequence. In embodiments, the C-terminal KIBRA compound includes a cyclic transportan amino acid sequence.In embodiments, the C-terminal KIBRA compound includes a hydrocarbon stapling sequence. In embodiments, the C-terminal KIBRA compound includes a glycine flexible linker. In embodiments, the C-terminal KIBRA compound includes a biotin amino acid sequence.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:6.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:7. In embodiments, the C- terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:8. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:9. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:10. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:11. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:12. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:13.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:14. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:15. In embodiments, the C- terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:16. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:17. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:18. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:19. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:20.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:21. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:22. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:23. In embodiments, the C- terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:24. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:25. [0169] In embodiments, at least one of the amino acids of the C-terminal KIBRA compound is a non-natural amino acid analog.
  • At least two of the amino acids of the C- terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least three of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least four of the amino acids of the C-terminal KIBRA compound are non- natural amino acid analogs. In embodiments, at least five of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least six of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least seven of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least eight of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least nine of the amino acids of the C- terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 10 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 11 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 12 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 13 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least 14 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 15 of the amino acids of the C-terminal KIBRA compound are non- natural amino acid analogs. In embodiments, at least 16 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 17 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 18 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 19 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least 20 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 21 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 22 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 23 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 24 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 25 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least 26 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 27 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 28 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 29 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 30 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 31 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least 32 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 33 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 34 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 35 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 36 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 37 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least 38 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 39 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 40 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. [0170] In embodiments, the C-terminal KIBRA compound includes at least one non-natural amino acid analog. In embodiments, the C-terminal KIBRA compound includes at least two non- natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least three non-natural amino acid analogs.
  • the C-terminal KIBRA compound includes at least four non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least five non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least six non-natural amino acid analogs. In embodiments, the C- terminal KIBRA compound includes at least seven non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least eight non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least nine non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 10 non- natural amino acid analogs.
  • the C-terminal KIBRA compound includes at least 11 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 12 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 13 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 14 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 15 non-natural amino acid analogs. In embodiments, the C- terminal KIBRA compound includes at least 16 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 17 non-natural amino acid analogs.
  • the C-terminal KIBRA compound includes at least 18 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 19 non- natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 20 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 21 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 22 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 23 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 24 non-natural amino acid analogs.
  • the C- terminal KIBRA compound includes at least 25 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 26 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 27 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 28 non- natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 29 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 30 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 31 non-natural amino acid analogs.
  • the C-terminal KIBRA compound includes at least 32 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 33 non-natural amino acid analogs. In embodiments, the C- terminal KIBRA compound includes at least 34 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 35 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 36 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 37 non- natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 38 non-natural amino acid analogs.
  • the C-terminal KIBRA compound includes at least 39 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 40 non-natural amino acid analogs. [0171] In embodiments, the C-terminal KIBRA compound does not include a N-terminal KIBRA peptide. In embodiments, the C-terminal KIBRA compound does not include the sequence of SEQ ID NO:29. In embodiments, the C-terminal KIBRA compound is not the sequence of SEQ ID NO:29.
  • C-TERMINAL KIBRA COMPOUNDS [0172] The methods provided herein include administration of a C-terminal KIBRA compound as provided herein including embodiments thereof.
  • a C- terminal KIBRA compound including a C-terminal KIBRA peptide including the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, wherein (a) at least one of the amino acids of the C-terminal KIBRA peptide is a non-natural amino acid analog; and/or (b) the C-terminal KIBRA compound further includes a TAT amino acid sequence, a penetratin amino acid sequence, an oligoarginine amino acid sequence, a xentry amino acid sequence, a transportan amino acid sequence, a cyclic-TAT amino acid sequence, a cyclic penetratin amino acid sequence, a cyclic oligoarginine amino acid sequence, a cyclic xentry amino acid sequence, a cyclic transportan amino acid sequence, a glycine flexible linker, or a biotin amino acid sequence.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:1. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:2. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:3. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:4. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:5.
  • the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5.
  • the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:1.
  • the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:2.
  • the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:3.
  • the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:4.
  • the C-terminal KIBRA compound is the amino acid sequence of SEQ ID NO:5.
  • At least one of the amino acids of the C-terminal KIBRA compound is a non-natural amino acid analog. In embodiments, at least two of the amino acids of the C- terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least three of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least four of the amino acids of the C-terminal KIBRA compound are non- natural amino acid analogs. In embodiments, at least five of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least six of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least seven of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least eight of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least nine of the amino acids of the C- terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 10 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 11 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 12 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least 13 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 14 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 15 of the amino acids of the C-terminal KIBRA compound are non- natural amino acid analogs. In embodiments, at least 16 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 17 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 18 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least 19 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 20 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 21 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 22 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 23 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 24 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least 25 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 26 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 27 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 28 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 29 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 30 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least 31 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 32 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 33 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 34 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 35 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 36 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs.
  • At least 37 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 38 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 39 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. In embodiments, at least 40 of the amino acids of the C-terminal KIBRA compound are non-natural amino acid analogs. [0175] In embodiments, the C-terminal KIBRA compound includes at least one non-natural amino acid analog. In embodiments, the C-terminal KIBRA compound includes at least two non- natural amino acid analogs.
  • the C-terminal KIBRA compound includes at least three non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least four non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least five non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least six non-natural amino acid analogs. In embodiments, the C- terminal KIBRA compound includes at least seven non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least eight non-natural amino acid analog. In embodiments, the C-terminal KIBRA compound includes at least nine non-natural amino acid analogs.
  • the C-terminal KIBRA compound includes at least 10 non- natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 11 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 12 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 13 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 14 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 15 non-natural amino acid analogs. In embodiments, the C- terminal KIBRA compound includes at least 16 non-natural amino acid analogs.
  • the C-terminal KIBRA compound includes at least 17 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 18 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 19 non- natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 20 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 21 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 22 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 23 non-natural amino acid analogs.
  • the C-terminal KIBRA compound includes at least 24 non-natural amino acid analogs. In embodiments, the C- terminal KIBRA compound includes at least 25 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 26 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 27 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 28 non- natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 29 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 30 non-natural amino acid analogs.
  • the C-terminal KIBRA compound includes at least 31 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 32 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 33 non-natural amino acid analogs. In embodiments, the C- terminal KIBRA compound includes at least 34 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 35 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 36 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 37 non- natural amino acid analogs.
  • the C-terminal KIBRA compound includes at least 38 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 39 non-natural amino acid analogs. In embodiments, the C-terminal KIBRA compound includes at least 40 non-natural amino acid analogs. [0176] In embodiments, the C-terminal KIBRA compound includes a cell-penetrating peptide or a blood-brain barrier-penetrating peptide. In embodiments, the C-terminal KIBRA compound includes a cell-penetrating peptide. In embodiments, the C-terminal KIBRA compound includes a blood-brain barrier-penetrating peptide.
  • the C-terminal KIBRA compound further includes a TAT amino acid sequence, a penetratin amino acid sequence, an oligoarginine amino acid sequence, a xentry amino acid sequence, a transportan amino acid sequence, a cyclic- TAT amino acid sequence, a cyclic penetratin amino acid sequence, a cyclic oligoarginine amino acid sequence, a cyclic xentry amino acid sequence, a cyclic transportan amino acid sequence, a hydrocarbon stapling sequence, a glycine flexible linker, or a biotin amino acid sequence.
  • the C-terminal KIBRA compound further includes a TAT amino acid sequence.
  • the C-terminal KIBRA compound further includes a penetratin amino acid sequence. In embodiments, the C-terminal KIBRA compound further includes a oligoarginine amino acid sequence. In embodiments, the C-terminal KIBRA compound further includes a xentry amino acid sequence.In embodiments, the C-terminal KIBRA compound further includes a transportan amino acid sequence. In embodiments, the C-terminal KIBRA compound further includes a cyclic-TAT amino acid sequence. In embodiments, the C-terminal KIBRA compound further includes a cyclic penetratin amino acid sequence. In embodiments, the C-terminal KIBRA compound further includes a cyclic oligoarginine amino acid sequence.
  • the C-terminal KIBRA compound further includes a cyclic xentry amino acid sequence. In embodiments, the C-terminal KIBRA compound further includes a cyclic transportan amino acid sequence.In embodiments, the C-terminal KIBRA compound further includes a hydrocarbon stapling sequence. In embodiments, the C-terminal KIBRA compound further includes a glycine flexible linker. In embodiments, the C-terminal KIBRA compound further includes a biotin amino acid sequence.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:6.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:7. In embodiments, the C- terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:8. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:9. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:10. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:11. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:12. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:13.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:14. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:15. In embodiments, the C- terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:16. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:17. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:18. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:19. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:20.
  • the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:21. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:22. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:23. In embodiments, the C- terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:24. In embodiments, the C-terminal KIBRA compound includes the amino acid sequence of SEQ ID NO:25.
  • PHARMACEUTICAL COMPOSITIONS [0178] The compositions provided herein include pharmaceutical compositions including the C-terminal KIBRA peptides provided herein including embodiments thereof.
  • a pharmaceutical composition comprising a therapeutically effective amount of a C-terminal KIBRA compound provided herein including embodiments thereof and a pharmaceutically acceptable excipient.
  • Pathogenic tau obstructs glutamatergic synapse function by blocking long-term potentiation (LTP), representing a key mechanism underlying memory impairment in Alzheimer’s disease (AD).
  • LTP long-term potentiation
  • CT-KIBRA C-terminus of KIBRA
  • CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss in the transgenic mouse brain, instead, we show that CT-KIBRA binds to and stabilizes protein kinase M ⁇ (PKM ⁇ ) to maintain plasticity and memory despite tau pathogenesis. Further, in humans we that KIBRA levels in brain and cerebrospinal fluid correlate with tau and cognitive impairment in tauopathies. Our study provides evidence to support KIBRA as a tauopathy-related synaptic biomarker and a synapse repair therapeutic to ameliorate cognitive impairment.
  • Pathological tau protein accumulates and forms aggregates in the brain in neurodegenerative diseases classified as tauopathies, including Alzheimer’s disease (AD), Pick’s disease, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP).
  • AD Alzheimer’s disease
  • CBD corticobasal degeneration
  • PSP progressive supranuclear palsy
  • Aberrant tau posttranslational modifications (PTMs) found in tauopathy brains can alter tau protein function, promote tau aggregation, and trigger toxicity in cells 1,2 .
  • the extent of pathologically modified tau that accumulates in human brain correlates with dementia severity in disease 3,4 . Tau is predominantly localized within axons of healthy neurons, whereas an abundance of pathological tau with PTMs is found at synapses in AD brain 5-7 .
  • LTP Long-term potentiation
  • tauopathy mouse models that precedes neurodegeneration and coincides with the start of cognitive impairments 8-10 .
  • LTP Long-term potentiation
  • tau is inhibited by tau with mutations that cause familial frontotemporal dementia 8,10,11 , as well as several AD-associated pathogenic forms of tau including hyperacetylated tau 9 , hyperphosphorylated tau 12,13 , and tau oligomers 14,15 .
  • Synapses, and their ability to express LTP are particularly vulnerable to tau-induced toxicity in the brain.
  • KIdney/BRAin is a postsynaptic protein encoded by the WWC1 gene that has a single nucleotide polymorphism linked to memory and risk of late-onset AD in humans 16-19 .
  • the KIBRA protein is required for hippocampal LTP and memory in mice 20 , and it contains multiple functional domains acting as a postsynaptic scaffold with approximately twenty binding partners identified 21,22 , supporting a critical role for KIBRA in modulating synaptic signaling and strength.
  • KIBRA protein is significantly diminished in the brain of severely impaired individuals with AD and reduced KIBRA levels are associated with abnormal hyperacetylated tau 9 .
  • a mimic of hyperacetylated human tau expressed in transgenic mice obstructs LTP by reducing KIBRA levels at synapses 9 , supporting that the loss of KIBRA function at synapses at least in part underlies AD-related plasticity and memory impairments.
  • tauKQ high mice obstructs LTP by reducing KIBRA levels at synapses 9 , supporting that the loss of KIBRA function at synapses at least in part underlies AD-related plasticity and memory impairments.
  • CT-KIBRA C-terminal domain
  • CT-KIBRA atypical protein kinase C
  • AMPARs postsynaptic type glutamate receptors
  • RESULTS A functional domain of the KIBRA protein reverses AD-related synapse dysfunction
  • FOG.1A To dissect the functional effect of the KIBRA protein on tau-mediated synapse dysfunction, we generated constructs to express flag-tagged full-length human KIBRA or truncated forms of the KIBRA protein in neurons (FIG.1A).
  • Neurons were transfected with either of the truncated KIBRA constructs together with human tau carrying lysine to glutamine mutations at lysine-274 and lysine-281 (tauKQ) to mimic hyperacetylated pathogenic tau found in Alzheimer’s disease 9 .
  • a chemical induction method involving glycine treatment in the absence of magnesium, was applied to the neurons to induce LTP, which potentiates synapse function through recruitment of AMPARs to the surface of postsynaptic spines 32,33 .
  • CT-KIBRA lentivirus lenti-CT-KIBRA
  • lenti-control lenti-control
  • field recordings were performed in the dentate gyrus molecular layer with stimulation of the perforant pathway.
  • CT-KIBRA improves hippocampus-dependent memory in mice with pathogenic tau despite tauopathy-related pathology
  • TauKQ high mice have hippocampus- dependent pattern separation memory loss by 6-7 months of age coinciding with the LTP deficit in dentate gyrus 9 .
  • ntg lenti-control, taukQ high lenti-control, and tauKQ high lenti-CT-KIBRA mice spent a greater fraction of time in the target quadrant in the probe trial 24 h after the hidden platform training was completed (FIGS.2E-2F).
  • ntg lenti-control and tauKQ high lenti- CT-KIBRA mice maintained a significant preference for the target quadrant probe trial after 7 days, whereas tauKQ high lenti-control mice did not (FIGS.2E and 2G), indicating that CT- KIBRA reversed the long-term spatial memory impairment in tauKQ high mice.
  • CT-KIBRA enhances multiple forms of hippocampus-dependent memory that are compromised by pathogenic tau in the brain.
  • CT-KIBRA mitigates pathology in the brain caused by expression of the acetylated tau mimic.
  • CT-KIBRA did not prevent the accumulation of phosphorylated tau at serine 202/205 (AT8) that was significantly increased in mossy fibers in the hippocampus of tauKQ high mice.
  • Synaptic vesicle associated protein 2 (SV2) has been used as an in vivo marker of synapse loss in human Alzheimer’s disease brain 34,35 .
  • SV2 synaptic vesicle associated protein 2
  • CT- KIBRA is sufficient to restore hippocampal synaptic plasticity, it is not sufficient to reverse tau- mediated synapse loss in the CA1 region.
  • Mass spectrometry analysis of protein extracted from whole hippocampus of tauKQ high lenti-control and tauKQ high lenti-CT-KIBRA mice was performed to monitor changes in the global proteome compared to ntg lenti-control mice (FIG. 8A and Table 1). Notably, of the 64 hits identified that were either significantly increased or decreased in tauKQ high compared to ntg mice, 33% of them changed in the hippocampi of both tauKQ high lenti-control and tauKQ high lenti-CT-KIBRA mice. A comparison of tauKQ high mice with or without CT-KIBRA also yielded no significant differences (Q ⁇ 0.05) in the abundance of the proteins that were identified (Table 1).
  • CT-KIBRA restores synaptic plasticity and reverses tau-induced memory impairment without altering levels of pathological tau in the brain and without recovering CA1 synapses lost in the hippocampus.
  • CT-KIBRA stabilizes and enhances PKM ⁇ at synapses with pathogenic tau
  • PICK1 which modulates AMPAR trafficking during plasticity 20 .
  • PAM proximity ligation assay
  • CT-KIBRA protects against PKM ⁇ downregulation associated with plasticity and memory impairments
  • a persistent increase in PKM ⁇ levels occurs in rodent neurons after LTP induction and learning 24,38-41 .
  • PKM ⁇ levels were increased within spines 24 h after chemical LTP induction compared to neurons that were not stimulated (FIG.4), in agreement with previous findings in cultured neurons 41 .
  • PICK1 was evaluated in the same mice, but the the PICK1 levels were not significantly different in tauKQ high lenti-control mice compared to ntg lenti-control mice (FIGS.10C-10D).
  • Experiments using acute PKM ⁇ knockdown in hippocampus suggest that PKM ⁇ plays a role in the maintenance of hippocampal dependent long-term memory 40,42 , and the magnitude of PKM ⁇ enhancement after learning correlates with the capacity for long-term memory in mice 40 . Consistent with these studies we found a significant correlation between hippocampal PKM ⁇ levels and long-term memory among the ntg lenti-control, tauKQ high lenti-control, and tauKQ high lenti-CT-KIBRA mice.
  • CT-KIBRA-AAA mutant in which three residues, R965, S967 and R969, on the CT-KIBRA construct were changed to alanine residues (R965A, S967A and R969A), which block the binding of KIBRA to PKM ⁇ 29 .
  • PLA method in HEK293 cells, we confirmed that compared to wildtype CT-KIBRA, CT-KIBRA-AAA demonstrated a significantly diminished interaction with HA-PKM ⁇ (FIG. 5C).
  • the CT-KIBRA-AAA mutant was detected in dendritic spines similarly to wildtype CT- KIBRA (FIG.11B).
  • CT-KIBRA overcomes the plasticity impairment caused by pathogenic tau by promoting synaptic resilience through its interaction with and modulation of PKM ⁇ (FIG.5E).
  • KIBRA levels in human brain and CSF are associated with pathological tau and cognitive impairment in older adults
  • KIBRA levels are significantly diminished in the brain in adults with severe Alzheimer’s disease compared to non-demented controls 9 .
  • CDR Global Clinical Dementia Rating
  • KIBRA levels were significantly reduced in individuals with moderate-to-severe dementia (CDR 2-3) compared to those with none-to-mild (CDR 0-1) impairment (FIG.6D).
  • CDR 2-3 moderate-to-severe dementia
  • CDR 0-1 none-to-mild impairment
  • FIG.6E total PKM ⁇ levels were reduced in only some of the cases with more advanced dementia compared to CDR 0-1 cases, and overall there was no significant difference in PKM ⁇ levels between the mild and impaired groups.
  • Comparisons were also made using the CDR sum of box (CDRsum) scores, which enables more continuous characterization of the extent of functional impairment 45,46 .
  • KIBRA levels in control, Alzheimer’s disease and Pick’s disease brains were strongly correlated with the CDRsum score, with the most impaired individuals having the least amount of KIBRA in the brain (FIG.6F).
  • the correlational analysis of PKM ⁇ levels with CDRsum did not reach statistical significance (FIG.6G).
  • the levels of both KIBRA and PKM ⁇ are linked to pathogenic tau in the brain in tauopathy, the total levels of KIBRA in the brain are more strongly associated with the clinical stage of dementia compared to PKM ⁇ levels.
  • Synaptic proteins can be detected in human CSF 47 , including SNAP-25 48 and neurogranin 49,50 , and are showing promise as biomarkers of in vivo synapse function in humans.
  • KIBRA levels were compared to CSF tau biomarkers including phosphorylated tau (p-tau181) and total tau which are both increased in CSF of AD patients and strongly correlate with worsened cognition 52 .
  • CSF KIBRA was significantly increased in subjects with clinically elevated CSF p-tau181 (FIG.12B) 53 .
  • CSF KIBRA levels detected in CSF and increased p-tau 181 and total tau levels FIGGS.6H-6I.
  • KIBRA did not correlate with concentrations of A ⁇ 40, A ⁇ 42 or the ratio of A ⁇ 42/A ⁇ 40 in CSF (FIGS.6J, 12C-12D), indicating that CSF KIBRA is predominantly associated with biomarkers of tau pathology rather than with A ⁇ pathology.
  • CSF KIBRA was assessed as a synaptic biomarker related to cognition in AD.
  • MMSE Mini-Mental State Exam
  • CT-KIBRA The therapeutic effect of CT-KIBRA involved its binding to and stabilization of PKM ⁇ to promote postsynaptic AMPAR trafficking during plasticity, enabling synapses to maintain function and overcome the adverse effects of pathogenic tau.
  • Our study provides evidence that CT-KIBRA can have a therapeutic effect when expressed in hippocampus after the onset of memory loss caused by pathogenic tau. This supports that CT-KIBRA recovers memory processes by repairing the molecular signaling at synapses required for plasticity. Enhancement of KIBRA signaling could also have therapeutic potential broadly across different tauopathies.
  • CT-KIBRA improved synaptic plasticity and memory performance in a model of abnormal hyperacetylated tau, which is a common pathology found in most tauopathies including AD, Pick’s disease, CBD and PSP 2,23,54 .
  • CT-KIBRA also restored synaptic plasticity in neurons expressing human P301L tau, confirming the protective effect of CT-KIBRA against tau toxicity associated with FTD. Nonetheless, it will be important to evaluate the impact of CT-KIBRA on synapse dysfunction and cognition in other tauopathy and neurodegenerative disease models.
  • tau drives pathophysiology in neurons in disease are complex, involving not only synapse dysfunction and synapse loss 8-10,55,56 , but also dysregulation of axonal transport and axon initial segment function as well as axon degeneration 57-59 , altered mitochondrial bioenergetics 60 , nuclear transport disruption 61,62 , altered proteostasis 63 , and cytoskeletal destabilization 64,65 .
  • CT-KIBRA did not affect tau levels or synapse loss in hippocampus, it likely plays a specific role in modulating synaptic plasticity without impacting other tau-mediated pathophysiological outcomes.
  • KIBRA deficient mice have reduced PKM ⁇ protein levels in the hippocampus, and impaired plasticity and memory loss 29,66 , which is consistent with a key role for KIBRA in PKM ⁇ stabilization and the maintenance of synaptic plasticity.
  • Our results show that tauKQ high mice, which have reduced KIBRA at synapses 9 , also had decreased PKM ⁇ levels in hippocampus associated with impaired LTP and hippocampus-dependent memory.
  • CT-KIBRA had a protective effect by restoring levels of PKM ⁇ . The strong relationship between KIBRA and PKM ⁇ protein levels was further evident in human brain with and without pathology.
  • Hyperacetylated tau correlated with lower levels of soluble KIBRA and PKM ⁇ proteins in tauopathy brains, supporting the mechanistic link between pathological tau and downregulation of KIBRA and PKM ⁇ . Aggregates of PKM ⁇ have been observed in neurofibrillary tangles containing hyperphosphorylated tau in AD brain 67 , but whether KIBRA is also bound to PKM ⁇ - containing insoluble aggregates is unknown. Strikingly, there was a prominent correlation between KIBRA downregulation in human brain and dementia severity, supporting KIBRA as a critical synaptic component linked to cognitive decline in tauopathy.
  • CT-KIBRA restores potentiation at synapses both by elevating PKM ⁇ levels and by enabling an additional activity- dependent signal, which remains to be determined, that drives the AMPAR recruitment after LTP induction.
  • CT-KIBRA may also modify synapse strength through binding to other PKC isoforms implicated in synaptic plasticity regulation, such as PKC ⁇ , ⁇ , ⁇ , and ⁇ , which were reduced in postsynaptic fractions prepared from KIBRA knockout mice 66 .
  • PKC ⁇ , ⁇ , ⁇ , and ⁇ implicated in synaptic plasticity regulation
  • PKC ⁇ , ⁇ , ⁇ , and ⁇ were reduced in postsynaptic fractions prepared from KIBRA knockout mice 66 .
  • the KIBRA protein has multiple functional domains that engage in interactions with numerous postsynaptic proteins to modulate synapse function, and here we identified a specific KIBRA domain and interaction that can have a beneficial impact in the context of disease.
  • the N-terminal WW domains of KIBRA bind to dendrin, and an inhibitory peptide that blocks this interaction reduced KIBRA levels and AMPARs at synapses on neurons, blocked LTP, and impaired memory in mice 27 , indicating that the interaction between KIBRA and dendrin regulates synaptic KIBRA localization and plasticity.
  • NT-KIBRA comprised of only the WW domains, in neurons and detected it in dendritic spines, although to a lesser degree compared to full-length KIBRA, and it did not rescue LTP in neurons with pathogenic tau. This suggests that while the dendrin/KIBRA WW domain interaction is necessary for plasticity in healthy neurons, it is not sufficient to reverse the plasticity impairment caused by pathogenic tau.
  • the binding of KIBRA to PICK1 can also modulate activity-dependent AMPAR trafficking in neurons 20 .
  • the higher KIBRA levels detected in CSF may be linked to the downregulation of KIBRA in the synaptic compartment in tauopathies.
  • KIBRA may be expelled from neurons with dysfunctional synapses and accumulate in the CSF, but the mechanisms underlying the changes in KIBRA levels at synapses and in CSF are unclear.
  • Our findings are consistent with prior studies showing higher SNAP-25, synaptotagmin-1, GAP-43, and neurogranin levels in CSF are associated with cognitive impairment in AD 48-50 , which may be linked to synapse degeneration in the brain 69 .
  • CT-KIBRA-mediated synapse repair could be valuable approach in combination with pathology-modifying strategies designed to slow progression of cognitive decline by reducing tau levels or clearing toxic forms of tau from the brain which are being tested in ongoing clinical trials 70,71 .
  • Our work supports a KIBRA-based synapse repair therapy that could promote the recovery of cognition in tauopathy with treatment by boosting the resilience of synapse function.
  • mice TauKQ high mice were previously generated (Tracy et al., 2016) and maintained in the C57BL/6 genetic background. TauKQ high mice were crossed with FVB/N mice (Jackson Laboratories) to generate TauKQ high mice in a FVB/N and C57BL/6 mixed background for experiments. Behavior experiments were performed in daylight hours. Mice were housed in a pathogen-free barrier facility with a 12h light-dark cycle and provided with ad libitum access to water and food. Female and male mice were used in all experiments. All animal procedures were completed under the supervision of the Buck Institute Research on Aging Institutional Animal Care and Use Committee.
  • Antibodies Monoclonal antibodies used included: AT270 (MN1050, Thermo Fisher Scientific, RRID: AB_223651), AT180 (MN1040, Thermo Fisher Scientific, RRID: AB_223649), HT7 (MN1000, Thermo Fisher Scientific, RRID: AB_2314654), Tau5 (AHB0042, Thermo Fisher Scientific, RRID: AB_2536235), Mab359 (from Dr.
  • Chemical LTP experiments were performed at 14-15 DIV in extracellular solution (ECS) containing (in mM): 125 NaCl, 5 KCl, 25 HEPES, 1 NaH2PO4, 11 Glucose, 2.5 CaCl2, 0.0005 tetrodotoxin, 0.1 picrotoxin, and 0.001 strychnine (pH 7.4) warmed to 37°C.
  • ECS extracellular solution
  • Neurons were briefly washed in ECS then transferred to ECS containing 300 ⁇ M Glycine for 5 min at room temperature to induce chemical LTP while unstimulated neurons were washed with ECS. After chemical LTP induction, all neurons were washed with ECS and incubated for 10 min at 37°C.
  • Coverslips were treated with anti-GluA1 antibody (ABN241, Sigma) in ECS for 15 min at 37°C. After antibody labeling, neurons were briefly washed with ECS then fixed in 4% paraformaldehyde (PFA). Coverslips were washed three times in PBS then incubated in blocking solution containing PBS, 2% normal goat serum, and 0.1% Triton X-100 for 1 h. An anti-rabbit conjugated Alexa 647 (Invitrogen) secondary antibody was applied for 1 h at room temperature then the coverslips were washed three times in PBS.
  • Alexa 647 Invitrogen
  • GFP-TauKQ or GFP-tauP301L neurons were labeled with anti-GFP conjugated to Alexa 488 (A21311, Invitrogen) to enhance the GFP signal. Coverslips were mounted on glass slides in Prolong Gold (Invitrogen). Images of transfected neurons were acquired on a Zeiss LSM 700 confocal microscope. Laser power and gain settings were kept constant across neurons within an experiment. Settings were established to keep the brightest pixel intensities just below saturation, except when the morphology of dendritic spines had to be clearly defined (e.g., saturated pixels of mApple fluorescence in dendrites to detect the signal in spines).
  • the collected media containing the lentivirus was purified using sucrose gradient ultracentrifugation.
  • the purified lentivirus was resuspended in sterile PBS and stored at -80 ⁇ C.
  • Lentivirus titer was estimated using a p24 Rapid Titer Kit (Takara Bio USA, Inc). Mice were anesthetized by isoflurane inhalation, and a stereotax was used to position the lentivirus injection directly into the mouse hippocampus using the following coordinates from bregma: anterior-posterior: -2.0, medial-lateral ⁇ 1.5, dorsal-ventral -1.8.
  • mice received analgesic treatment with buprenorphine with one dose at the start of the surgery and two additional doses within 24 h after surgery.
  • Acute Slice Preparation [0226] Mouse brains were quickly dissected into cold sucrose dissection solution containing (in mM): 210 sucrose, 2.5 KCl, 1.25 NaH2PO4, 25 NaHCO3, 7 glucose, 2 MgSO4, and 0.5 CaCl2 (perfused with 95% O2, 5% CO2 with ph ⁇ 7.4).
  • Recording electrodes ( ⁇ 3 megaohms resistance) were filled with ACSF and lowered 50 ⁇ m into the dorsal blade of the molecular layer of the dentate gyrus.
  • a bipolar tungsten electrode (FHC) was positioned ⁇ 150 ⁇ m away from the recording electrode to stimulate the perforant pathway inputs to the dentate gyrus.
  • Stimulus pulses were elicited at an intensity range from 0.25 ⁇ A – 25 ⁇ A every 30 seconds with a 0.5 ms stimulus duration using a Model 2100 Isolated Pulse Stimulate (A-M Systems) to acquire the maximal fEPSP slope. The stimulus intensity was adjusted to 30% of the maximal fEPSP slope to record the baseline for LTP recordings.
  • mice were habituated in the testing room while in their home cage for 30 min before the start of testing. During the sample phase, mice explored two similar, but distinct contexts in two different 10 min sessions that were 30 min apart.
  • Context 1 was a white box that was cleaned with 70% ethanol.
  • Context 2 was a white box with black and white checkered wallpaper on the 4 walls that was cleaned with 1% acetic acid.
  • Context 1 contained two identical blue cylindrical containers (X1 and X2)
  • Context 2 contained two identical T25 flasks filled with yellow sand (Y 1 and Y 2 ).
  • the mice were returned to their home cages for 4 h after the sample phase.
  • one of the X objects in Context 1 was replaced with an incongruent Y object
  • one of the Y objects in Context 2 was replaced with an incongruent X object.
  • Y-maze arena was constructed with plexiglass having three arms of equal length (20 cm) at equal angles. Mice were placed in the center and allowed to freely explore the arena for 5 min and recorded by video (Noldus). Each mouse was manually scored for the sequence and number of arm entries in the 5-min period and the experimenter was blind to the genotype and treatment of each mouse. An arm entry was defined as having all four paws within one arm. The percentage of spontaneous alternations for each mouse was calculated as the number of alternations divided by the total possible number of alternations in the 5-min session.
  • An alternation is defined as the mouse having entered all three arms in succession without revisiting a previously entered arm.
  • the Morris water maze used a pool with a diameter of 120 cm and filled with water at a temperature 22 ⁇ 1 ⁇ C made opaque by the addition of white tempera paint. Visual cues were placed around the pool. The experimenter was blind to the genotype and treatment of each mouse. Mice were pretrained for one day with 4 trials to find a submerged hidden square platform (14 cm x 14 cm) that was 1.5 cm below the water surface located in the center of a rectangular channel. The day after pretraining, each mouse performed 4 days of hidden platform training with 2 trials per day where they had 60 seconds to find and sit independently on the platform for 10 s.
  • Homogenized tissue was sonicated 20 times with 1 sec pulses and then centrifuged using a SW55 Ti rotor (Beckman Coulter) at 42,700 rpm for 15 min at 4°C.
  • Mouse tissue was homogenized in RIPA buffer containing 50 mM Tris-HCl pH 7.5, 0.5% Nonidet P-40, 150 mM NaCl, 1 mM EDTA, 1 mM phenylmethyl sulfonyl fluoride, protease inhibitor cocktail (Sigma), phosphatase inhibitor cocktail 2 (Sigma) and phosphatase inhibitor cocktail 3 (Sigma).
  • Tissue was homogenized with a hand-held homogenizer for 2 min and sonicated 10 times with 1 sec pulses.
  • Lysates were then incubated on ice for 30 min and centrifuged at 18,000 g at 4 ⁇ C for 20 min. The supernatants were collected from human or mouse brain homogenates after centrifugation and the protein concentration was measured by Bradford Assay (Bio-Rad). Equal amounts of proteins were run on a 4-12% gradient SDS-PAGE gel (Invitrogen) and the protein was transferred to a nitrocellulose membrane (GE Healthcare). The membranes were blocked with 5% nonfat dry milk in TBST for at room temperature for 1 hr followed by incubation with primary antibodies in TBST with 2% nonfat dry milk overnight at 4 ⁇ C.
  • the flag-tagged CT-KIBRA sequence was inserted into FUGW2 (Gladstone Institutes) and packaged into virus using ⁇ 8.9 and VSV-G plasmids.
  • HA-tagged PKM ⁇ and HA-tagged PICK1 were cloned into pcDNA 3.1 from human cDNA plasmids verified by sequencing (SinoBiological).
  • GFP-tagged human tauKQ and tauP301L were expressed from the pEGFP-C1 plasmid (Clontech). Expression of mApple or GFP in cultured neurons was done using pGW1-mApple and pEGFP-C1 plasmids, respectively.
  • CT-KIBRA-AAA mutant was generated by site-directed mutagenesis of CT- KIBRA in pcDNA3.1 (Genscript).
  • Antisense Oligonucleotide [0240] Antisense oligonucleotides against PKMzeta (C*T*C*TTGGGAAGGCAT*G*A*C) and scrambled oligonucleotides (A*A*C*AATGGGTCGTCT *C*G*G) were generated (IDT) with phosphorothioate bonds (*).
  • rat neurons were preincubated with oligonucleotides (20 ⁇ M final) for 1 h before chemical LTP, and the oligonucleotides remained in the media for the duration of the chemical LTP experiment.
  • Immunohistochemistry [0242] Mouse brain sections (30-40 mm) were used for immunohistochemistry. For AT8 immunostaining, sections were washed with PBS and heated to 95 ⁇ C for 5 min in 10 mM Sodium Citrate for antigen retrieval, followed by incubation at room temperature for 20 min. Sections were washed with PBS and incubated in blocking solution (PBST with 10% normal goat serum) for 2 h at room temperature.
  • PBST blocking solution
  • HEK cells were transfected 24 h later with plasmid DNA with Lipofectamine 2000 (Invitrogen).
  • HEK cells were fixed in 4% PFA 24 h after transfection and washed three times with PBS.
  • coverslips were blocked in Duolink blocking solution (DUO82007, Sigma) then labeled with primary antibodies and the secondary antibodies, anti-Rabbit PLUS (DUO92002, Sigma) and anti-Mouse MINUS (DUO92004, Sigma).
  • PLA signals were detected using the red Duolink in situ detection reagent kit (DUO92008, Sigma) and imaged on the Zeiss LSM700. Images were analyzed using ImageJ software.
  • Protein Stability Assay Plated 0.5 x 10 6 HEK293 cells on each well of a 12-well culture plate. The cells were then transfected with HA-PKMz or HA-PKMz and CT-KIBRA-flag using lipofectamine 2000 (Life Technologies). A day after transfection, untreated cells (0 hr timepoint) were harvested, while the rest of the cells were treated with 5 mg/ml of cycloheximide. Treated cells were then harvested after 24 and 48 h of incubation with cycloheximide.
  • CDR Chronic Dementia Rating
  • CDR range 0.5 to 2
  • CSF was collected via lumbar puncture in the morning following a 12-hour fast in sterile polypropylene tubes. Within 30 min of collection, CSF samples were centrifuged at 2000g at room temperature (20-25°C) for 5 min before being aliquoted into 500uL cryovials and stored at -80°C until analysis, following standard procedure 78 .
  • ELISAs [0253] Commercially available enzyme-linked immunosorbent assay (ELISA) kits were used to measure levels of KIBRA (Wuhan Fine Biotech Co., Ltd, China), p-tau181, t-tau (INNOTEST, USA), Ab40 and Ab42 (ThermoFisher, USA) in CSF samples. ELISAs on CSF were performed in duplicates and averaged. Samples with % CV > 20% were excluded from analyses.
  • Table 1 Patient information for human brain tissues described herein.
  • KIBRA modulates directional migration of podocytes. Journal of the American Society of Nephrology : JASN 19, 1891-1903, doi:10.1681/asn.2007080916 (2008). [0287] 29 Vogt-Eisele, A. et al. KIBRA (KIdney/BRAin protein) regulates learning and memory and stabilizes Protein kinase M ⁇ . Journal of neurochemistry 128, 686-700, doi:10.1111/jnc.12480 (2014). [0288] 30 Yoshihama, Y. et al. KIBRA suppresses apical exocytosis through inhibition of aPKC kinase activity in epithelial cells.
  • Alzheimer's & dementia the journal of the Alzheimer's Association 16, 974-982, doi:10.1002/alz.12097 (2020).
  • 36 Yoshihama, Y., Hirai, T., Ohtsuka, T. & Chida, K. KIBRA Co-localizes with protein kinase Mzeta (PKMzeta) in the mouse hippocampus. Bioscience, biotechnology, and biochemistry 73, 147-151, doi:10.1271/bbb.80564 (2009).
  • PLMzeta protein kinase Mzeta
  • KIBRA-PKC ⁇ signaling pathway modulates memory performance in mice and humans.2021.2010.2026.465926, doi:10.1101/2021.10.26.465926 %J bioRxiv (2021).
  • Atypical protein kinase C in neurodegenerative disease I PKMzeta aggregates with limbic neurofibrillary tangles and AMPA receptors in Alzheimer disease. Journal of neuropathology and experimental neurology 65, 319-326, doi:10.1097/01.jnen.0000218442.07664.04 (2006).
  • P Embodiment 1 A method of treating a tau-associated memory deficit disorder in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a C-terminal KIBRA compound. [0338] P Embodiment 2.
  • P Embodiment 3 A method of treating aging-associated cognitive decline in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a C-terminal KIBRA compound.
  • P Embodiment 4 The method of P embodiment 3, wherein the aging-associated cognitive decline occurs in the absence of tau-associated neurodegeneration.
  • P Embodiment 14 The method of P embodiment 1, wherein the C-terminal KIBRA peptide is between about 20 and about 40 amino acids in length.
  • P Embodiment 15 The method of P embodiment 1, wherein the C-terminal KIBRA peptide is between about 10 and about 20 amino acids in length.
  • P Embodiment 16 The method of P embodiment 1, wherein the C-terminal KIBRA peptide is between about 5 and about 10 amino acids in length.
  • the C- terminal KIBRA compound comprises a TAT amino acid sequence, a penetratin amino acid sequence, an oligoarginine amino acid sequence, a xentry amino acid sequence, a transportan amino acid sequence, a cyclic-TAT amino acid sequence, a cyclic penetratin amino acid sequence, a cyclic oligoarginine amino acid sequence, a cyclic xentry amino acid sequence, a cyclic transportan amino acid sequence, a hydrocarbon stapling sequence, a glycine flexible linker, or a biotin amino acid sequence.
  • P Embodiment 20 comprises a TAT amino acid sequence, a penetratin amino acid sequence, an oligoarginine amino acid sequence, a xentry amino acid sequence, a transportan amino acid sequence, a hydrocarbon stapling sequence, a glycine flexible linker, or a biotin amino acid sequence.
  • the C- terminal KIBRA compound comprises the amino acid sequence of SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25.
  • P Embodiment 21 comprises the amino acid sequence of SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID
  • P Embodiment 22 The method of any one of P embodiments 1-21, wherein the C- terminal KIBRA compound does not comprise the sequence of SEQ ID NO:29.
  • P Embodiment 23 The method of any one of P embodiments 1-20, wherein at least one of the amino acids of the C-terminal KIBRA compound is a non-natural amino acid analog.
  • a C-terminal KIBRA compound comprising the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, wherein (a) at least one of the amino acids of the C-terminal KIBRA peptide is a non-natural amino acid analog; and/or (b) the C-terminal KIBRA compound further comprises a TAT amino acid sequence, a penetratin amino acid sequence, an oligoarginine amino acid sequence, a xentry amino acid sequence, a transportan amino acid sequence, a cyclic-TAT amino acid sequence, a cyclic penetratin amino acid sequence, a cyclic oligoarginine amino acid sequence, a cyclic xentry amino acid sequence, a cyclic transportan amino acid sequence, a glycine flexible linker, or a biotin amino acid sequence.
  • P Embodiment 24 The C-terminal KIBRA compound of P embodiment 23, wherein the C-terminal KIBRA compound comprises the amino acid sequence of SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25.
  • P Embodiment 25 P Embodiment 25.
  • Embodiment 1 A method of treating a tau-associated memory deficit disorder in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a C-terminal KIBRA compound.
  • Embodiment 2. The method of embodiment 1, wherein the tau-associated memory deficit disorder is Alzheimer’s disease, progressive supranuclear palsy, Pick’s disease, corticobasal degeneration, chronic traumatic encephalopathy, or Frontotemporal lobar dementia- tau (FTLD-tau).
  • a method of treating aging-associated cognitive decline in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a C-terminal KIBRA compound.
  • Embodiment 4. The method of embodiment 3, wherein the aging-associated cognitive decline occurs in the absence of tau-associated neurodegeneration.
  • Embodiment 5. The method of embodiment 1, wherein the C-terminal KIBRA compound comprises a C-terminal KIBRA peptide.
  • Embodiment 6. The method of embodiment 5, wherein the C-terminal KIBRA peptide is between about 700 and about 800 amino acids in length.
  • Embodiment 8 The method of embodiment 5, wherein the C-terminal KIBRA peptide is between about 500 and about 600 amino acids in length.
  • Embodiment 9. The method of embodiment 5, wherein the C-terminal KIBRA peptide is between about 400 and about 500 amino acids in length.
  • Embodiment 10. The method of embodiment 5, wherein the C-terminal KIBRA peptide is between about 300 and about 400 amino acids in length.
  • Embodiment 11 The method of embodiment 5, wherein the C-terminal KIBRA peptide is between about 200 and about 300 amino acids in length.
  • Embodiment 12 The method of embodiment 5, wherein the C-terminal KIBRA peptide is between about 100 and about 200 amino acids in length.
  • Embodiment 13 The method of embodiment 5, wherein the C-terminal KIBRA peptide is between about 50 and about 100 amino acids in length.
  • Embodiment 14 The method of embodiment 5, wherein the C-terminal KIBRA peptide is between about 40 and about 50 amino acids in length.
  • Embodiment 15 The method of embodiment 5, wherein the C-terminal KIBRA peptide is between about 20 and about 40 amino acids in length.
  • Embodiment 17 The method of embodiment 5, wherein the C-terminal KIBRA peptide is between about 5 and about 10 amino acids in length.
  • Embodiment 18 The method of any one of embodiments 1-12, wherein the C- terminal KIBRA compound comprises the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3.
  • Embodiment 19 The method of any one of embodiments 1-18, wherein the C- terminal KIBRA compound comprises the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5.
  • Embodiment 20 The method of any one of embodiments 1-18, wherein the C- terminal KIBRA compound comprises the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5.
  • the C- terminal KIBRA compound comprises a TAT amino acid sequence, a penetratin amino acid sequence, an oligoarginine amino acid sequence, a xentry amino acid sequence, a transportan amino acid sequence, a cyclic-TAT amino acid sequence, a cyclic penetratin amino acid sequence, a cyclic oligoarginine amino acid sequence, a cyclic xentry amino acid sequence, a cyclic transportan amino acid sequence, a hydrocarbon stapling sequence, a glycine flexible linker, or a biotin amino acid sequence.
  • Embodiment 21 Embodiment 21.
  • the C- terminal KIBRA compound comprises the amino acid sequence of SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25.
  • Embodiment 22 comprises the amino acid sequence of SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO
  • Embodiment 23 The method of any one of embodiments 1-22, wherein the C- terminal KIBRA compound does not comprise the sequence of SEQ ID NO:29. [0385] Embodiment 24.
  • a C-terminal KIBRA compound comprising a C-terminal KIBRA peptide comprising the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, wherein (a) at least one of the amino acids of the C-terminal KIBRA peptide is a non-natural amino acid analog; and/or (b) the C-terminal KIBRA compound further comprises a TAT amino acid sequence, a penetratin amino acid sequence, an oligoarginine amino acid sequence, a xentry amino acid sequence, a transportan amino acid sequence, a cyclic-TAT amino acid sequence, a cyclic penetratin amino acid sequence, a cyclic oligoarginine amino acid sequence, a cyclic xentry amino acid sequence, a cyclic transportan amino acid sequence, a glycine flexible linker, or a biotin amino acid sequence.
  • Embodiment 25 The C-terminal KIBRA compound of embodiment 24, wherein the C-terminal KIBRA compound comprises the amino acid sequence of SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25.
  • Embodiment 26 A pharmaceutical composition comprising a therapeutically effective amount of a C-terminal KIBRA compound of embodiment 24 or 25 and a pharmaceutically acceptable excipient.

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Abstract

L'invention concerne, entre autres, des peptides KIBRA C-terminaux qui sont utiles pour traiter des troubles de déficit de mémoire associés à tau.<i /> L'invention concerne également des peptides KIBRA C-terminaux qui sont utiles pour traiter un déclin cognitif associé au vieillissement.
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