WO2024199436A1 - Molécule active polypeptidique ayant une demi-vie étendue et une stabilité améliorée - Google Patents

Molécule active polypeptidique ayant une demi-vie étendue et une stabilité améliorée Download PDF

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Publication number
WO2024199436A1
WO2024199436A1 PCT/CN2024/084773 CN2024084773W WO2024199436A1 WO 2024199436 A1 WO2024199436 A1 WO 2024199436A1 CN 2024084773 W CN2024084773 W CN 2024084773W WO 2024199436 A1 WO2024199436 A1 WO 2024199436A1
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Prior art keywords
tat
amino acids
glur2ct
active molecule
polypeptide
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Ceased
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PCT/CN2024/084773
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English (en)
Chinese (zh)
Inventor
王玉田
颜毅
耿传荣
邢晓旭
庄立群
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Qingdao Primedicine Pharmaceutical Co Ltd
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Qingdao Primedicine Pharmaceutical Co Ltd
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Priority to CN202480023870.2A priority Critical patent/CN120958011A/zh
Publication of WO2024199436A1 publication Critical patent/WO2024199436A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present invention belongs to the field of biomedicine. Specifically, the present invention relates to a polypeptide active molecule with extended half-life and improved stability, wherein the half-life and stability are increased by replacing L-type amino acids at specific positions with D-type amino acids.
  • PMS-001 (Tat-GluR2CT) is a peptide drug that can be used to treat acute stroke, drug addiction, Alzheimer's disease, and depression. It mainly interferes with the interaction between the key amino acid sequence at the C-terminus of the AMPA receptor and the Brag2 protein, thereby inhibiting the excessive endocytosis of the AMPA receptor, thereby achieving the treatment of abnormal neural signal conduction and related brain damage. Previous stroke experiments have shown that this peptide drug can significantly alleviate brain damage caused by short-term or long-term ischemia, and significantly reduce the occurrence of cognitive impairment and depression caused by stroke, so it has good clinical development prospects.
  • the PMS-001 peptide is composed of two amino acid sequences connected.
  • the functional sequence that plays a therapeutic role is the endogenous sequence GluR2-CT peptide (YKEGYNVYG), and the other sequence is the auxiliary functional sequence Tat transmembrane peptide (YGRKKRRQRRR) that crosses the blood-brain barrier and enters the brain smoothly through the cell membrane into the neuron.
  • GluR2-CT peptide YKEGYNVYG
  • YGRKKRRQRRR auxiliary functional sequence Tat transmembrane peptide
  • L-type amino acids constitute most of the protein composition in nature, and D-type amino acids only exist in a very small number of individual tissues, organs or proteins. Therefore, most proteolytic enzymes in animals generally have L-configuration specificity. Under the premise of ensuring biological activity, selectively replacing L-type amino acids with D-type amino acids will help increase the stability of the product in plasma.
  • FIG. 1 Plasma degradation profile of PMS-001 peptide (A) and potential degradation sites (B).
  • the present invention provides a modified Tat polypeptide having an amino acid sequence XGRKKRRQRRR (SEQ ID NO: 1), wherein X is absent or is Y, and one or more amino acids selected from R10, X1, R3, K4, K5, R6, R7, Q8, R9, R11 are D-amino acids, preferably, X is Y.
  • amino acids in the amino acid sequences of the invention are represented by single-letter designations commonly known in the art.
  • the modified Tat polypeptide has an amino acid sequence YGRKKRRQRRR (SEQ ID NO: 30), and one or more amino acids selected from R10, Y1, R3, K4, K5, R6, R7, Q8, R9, and R11 are D-amino acids.
  • amino acids or numbers may be used to represent the amino acids at specific positions.
  • X1 represents the amino acid residue X at position 1 of the polypeptide (e.g., X may not exist or may be Y)
  • R3 represents the amino acid residue R at position 3 of the polypeptide, and so on.
  • the remaining amino acid residues in the polypeptide are L-amino acids.
  • R10 and one or more amino acids selected from XI, R3, K4, K5, R6, R7, Q8, R9, R11 of the modified Tat polypeptide are D-amino acids.
  • R10 and one or more amino acids selected from R3, K4, K5, R6, and R7 of the modified Tat polypeptide are D-amino acids.
  • R10, one or more amino acids selected from R3, K4, K5, and one or more amino acids selected from R6, R7 of the modified Tat polypeptide are D-amino acids.
  • R10 and one or more amino acids selected from R3 and R6 of the modified Tat polypeptide are D-amino acids, preferably, R10, R3 and R6 of the modified Tat polypeptide are D-amino acids.
  • the modified Tat polypeptide has an amino acid sequence of YGR * KKR * RQRR * R (SEQ ID NO: 34).
  • R10 and one or more amino acids selected from K4 and R7 of the modified Tat polypeptide are D-amino acids, preferably, R10, K4 and R7 of the modified Tat polypeptide are D-amino acids.
  • the modified Tat polypeptide has an amino acid sequence of YGRK * KRR * QRR * R (SEQ ID NO: 35).
  • R10 and one or more amino acids selected from R3 and R7 of the modified Tat polypeptide are D-amino acids, preferably, R10, R3 and R7 of the modified Tat polypeptide are D-amino acids.
  • the modified Tat polypeptide has an amino acid sequence of YGR * KKRR * QRR * R (SEQ ID NO: 36).
  • R10 and one or more amino acids selected from R3, K5 and R7 of the modified Tat polypeptide are D-amino acids, preferably, R10, R3, K5 and R7 of the modified Tat polypeptide are D-amino acids.
  • the modified Tat polypeptide has an amino acid sequence of YGR * KK * RR * QRR * R (SEQ ID NO: 37).
  • K5, R6, R7, R9, R10, and R11 of the modified Tat polypeptide are D-amino acids.
  • R10 of the modified Tat polypeptide is a D-amino acid.
  • R10 and R9 of the modified Tat polypeptide are D-amino acids.
  • R10 and R11 of the modified Tat polypeptide are D-amino acids.
  • R10, R9, and R11 of the modified Tat polypeptide are D-amino acids.
  • R10, X1, R3, K4, K5, R6, R7, Q8, R9, and R11 of the modified Tat polypeptide are D-amino acids.
  • the present invention provides a reverse variant of the modified Tat polypeptide, which comprises an amino acid sequence opposite to that of the modified Tat polypeptide.
  • the sequence of the reverse variant is opposite to that of the modified Tat polypeptide (N-terminus-C-terminus are opposite), but the type of the corresponding amino acids remains unchanged.
  • the modified Tat polypeptide comprises an amino acid sequence of YGR * KKRRQRRR
  • its reverse variant comprises RRRQRRKKR * GY, wherein R * indicates that the amino acid residue R is a D-amino acid.
  • the modified Tat polypeptide has an amino acid sequence of YGR * KK * RR * QRR * R, then its reverse variant has RR * RQR * RK * KR * GY, wherein the amino acid superscript " * " indicates that the amino acid residue is a D-amino acid.
  • the modified Tat polypeptide or its reverse variant of the present invention substantially retains the cell membrane permeation activity of the wild-type Tat polypeptide (all of whose amino acid residues are L-amino acids), and in particular, when linked to a polypeptide of interest, substantially retains the ability to confer cell membrane permeation activity to the polypeptide of interest.
  • the modified Tat polypeptide or its reverse variant of the present invention has an increased half-life in vivo compared to the wild-type Tat polypeptide (all of whose amino acid residues are L-amino acids), and in particular, when linked to a polypeptide of interest, enables the obtained linked polypeptide to have an increased half-life in vivo.
  • the modified Tat polypeptide or its reverse variant has an increased half-life in vitro compared to the wild-type Tat polypeptide (all of whose amino acid residues are L-amino acids), and in particular, when linked to a polypeptide of interest, enables the obtained linked polypeptide to have an increased half-life in vitro.
  • in vivo half-life refers to the half-life in a subject, such as a human body.
  • the in vivo half-life can be predicted by an in vitro half-life, such as the half-life in ex vivo plasma or serum, or can be determined by methods known in the art.
  • the in vitro half-life of a polypeptide can be determined by the methods described in the Examples of the present invention.
  • polypeptide of interest refers to a polypeptide that is desired to be delivered (e.g., via a modified Tat polypeptide of the present invention) to a subject to exert a specific effect (e.g., prevent and/or treat a disease).
  • the polypeptide of interest is a therapeutic polypeptide.
  • therapeutic polypeptides include, but are not limited to, polypeptides shown in any one of SEQ ID NOs: 2-27 as shown in Table 1 below, or functional variants thereof.
  • the present invention provides use of the modified Tat polypeptide or inverse variant thereof for delivering a polypeptide of interest to a subject.
  • the polypeptide of interest is linked to the modified Tat polypeptide or an inverted variant thereof.
  • the polypeptide of interest is linked to the modified Tat polypeptide or inverted variant thereof via a chemical linker.
  • the chemical linker described herein can be any chemical linker shown in linking two polypeptides, for example, the chemical linker can be a PEG linker.
  • the polypeptide of interest is fused to the modified Tat polypeptide or an inverse variant thereof.
  • fusion refers to the connection of two polypeptides by a peptide bond between the terminal amino acids, and this term is distinguished from connection by a chemical linker.
  • the polypeptide of interest is fused to the modified Tat polypeptide or its inverse variant directly or through a peptide linker.
  • the modified Tat polypeptide or its inverse variant is located at the N-terminus of the polypeptide of interest.
  • the modified Tat polypeptide or its inverse variant is located at the C-terminus of the polypeptide of interest.
  • the present invention provides an active molecule comprising
  • i) and ii) are connected by a chemical linker.
  • the chemical linker is a PEG linker.
  • i) is fused to ii). In some embodiments, wherein i) and ii) are fused directly or via a peptide linker.
  • i) is located at the N-terminus of ii). In some embodiments, wherein i) is located at the C-terminus of ii).
  • the polypeptide of interest in ii) is a therapeutic polypeptide.
  • therapeutic polypeptides include, but are not limited to, polypeptides shown in any one of SEQ ID NO: 2-27 or functional variants thereof.
  • the polypeptide of interest in the active molecule of the present invention may also contain one or more D-amino acids to further increase the half-life of the active molecule.
  • the active molecule of the present invention containing D-amino acids substantially retains the cell membrane permeation activity of Tat and/or the activity of the polypeptide of interest, and has an increased half-life.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active molecule of the present invention and a pharmaceutically acceptable carrier.
  • the use of the pharmaceutical composition generally depends on the activity and/or function of the polypeptide of interest in the active molecule. Exemplary polypeptides of interest and their uses are shown in Table 1.
  • the present invention provides the use of the active molecule of the present invention in the preparation of a medicament.
  • the disease that the medicament can treat and/or prevent generally depends on the activity and/or function of the polypeptide of interest in the active molecule. Exemplary polypeptides of interest and their uses can be found in Table 1.
  • the present invention provides a method for treating a disease in a subject, comprising administering to the subject an effective amount of an active molecule of the present invention or a pharmaceutical composition of the present invention comprising the active molecule.
  • the disease generally depends on the activity and/or function of the polypeptide of interest in the active molecule. Exemplary polypeptides of interest and their uses are shown in Table 1.
  • GluR2-CT polypeptides have previously been shown to be useful for treating or preventing nerve damage or nerve dysfunction in a subject, and are therefore useful for treating or preventing nerve damage or nerve dysfunction caused by stress, anxiety, depression, hypoglycemia, cardiac arrest, epilepsy, cerebral ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropathic pain, amyotrophic lateral sclerosis (ALS), Hutchinson-Gilford syndrome, diabetes, ataxia, mental retardation, dementia, diseases associated with smoking or obesity, hypertension, diseases associated with learning or memory deficits or dysfunction, mental illness, autism, schizophrenia, fragile X syndrome, and diseases associated with drug abuse or drug addiction, see EP 1,687,427 B1.
  • R10, Y1, R3, K4, K5, R6, R7, Q8, R9 and R11 of the Tat-GluR2CT active molecule are D-amino acids.
  • R10, K13 and one or more amino acids selected from X1, R3, K4, K5, R6, R7, Q8, R9, and R11 of the Tat-GluR2CT active molecule are D-amino acids.
  • R10, K13 and one or more amino acids selected from R3, K4, K5, R6, and R7 of the Tat-GluR2CT active molecule are D-amino acids.
  • R10, K13, one or more amino acids selected from R3, K4, K5, and one or more amino acids selected from R6, R7 of the Tat-GluR2CT active molecule are D-amino acids.
  • R10, K13 and one or more amino acids selected from K4 and R7 of the Tat-GluR2CT active molecule are D-amino acids, preferably, R10, K13, K4 and R7 of the Tat-GluR2CT active molecule are D-amino acids.
  • the Tat-GluR2CT active molecule has an amino acid sequence of YGRK * KRR * QRR * RYK * EGYNVYG (SEQ ID NO: 39).
  • K5, R6, R7, R9, R10, R11, and K13 of the Tat-GluR2CT active molecule are D-amino acids.
  • R10 and K13 of the Tat-GluR2CT active molecule are D-amino acids.
  • R10, K13, R9 and R11 of the Tat-GluR2CT active molecule are D-amino acids.
  • Y1, R3, K4, K5, R6, R7, Q8, R9, R10, R11 and K13 of the Tat-GluR2CT active molecule are D-amino acids.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the Tat-GluR2CT active molecule of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprising the Tat-GluR2CT active molecule of the present invention is used in combination with tissue plasminogen activator (tPA) to treat and/or prevent stroke in a subject, such as ischemic stroke, drug addiction, relapse after drug addiction withdrawal, Alzheimer's disease, depression, anxiety, amyotrophic lateral sclerosis, hypoglycemia, epilepsy, brain injury, Parkinson's disease, Huntington's disease, neuropathic pain, intellectual disability, dementia, learning and memory deficiency and disorder syndrome, mental disorder, autism, schizophrenia, etc.
  • tissue plasminogen activator tPA
  • the present invention provides use of the Tat-GluR2CT active molecule of the present invention in preparing a drug.
  • the drug is used in combination with tissue plasminogen activator (tPA) to treat and/or prevent stroke in a subject, such as ischemic stroke, drug addiction, relapse after drug addiction withdrawal, Alzheimer's disease, depression, anxiety, amyotrophic lateral sclerosis, hypoglycemia, epilepsy, brain injury, Parkinson's disease, Huntington's disease, neuropathic pain, intellectual disability, dementia, learning and memory deficits and disorder syndromes, mental disorders, autism, schizophrenia, etc.
  • tissue plasminogen activator tPA
  • the drug further comprises tissue plasminogen activator (tPA), which is used to treat and/or prevent stroke in a subject, such as ischemic stroke, drug addiction, relapse after drug addiction withdrawal, Alzheimer's disease, depression, anxiety, amyotrophic lateral sclerosis, hypoglycemia, epilepsy, brain injury, Parkinson's disease, Huntington's disease, neuropathic pain, intellectual disability, dementia, learning and memory deficiency and disorder syndrome, mental disorder, autism, schizophrenia, etc.
  • tissue plasminogen activator tPA
  • the present invention provides a method for treating and/or preventing a disease in a subject, comprising administering to the subject an effective amount of the Tat-GluR2CT active molecule of the present invention or a pharmaceutical composition comprising the Tat-GluR2CT active molecule of the present invention.
  • the method further comprises administering to the subject an effective amount of tissue plasminogen activator (tPA).
  • tPA tissue plasminogen activator
  • the disease is a disease that causes nerve damage or nerve dysfunction.
  • the disease is a stroke such as ischemic stroke or hemorrhagic stroke, drug addiction, relapse after drug addiction withdrawal, Alzheimer's disease, depression, anxiety, amyotrophic lateral sclerosis, hypoglycemia, epilepsy, brain injury, Parkinson's disease, Huntington's disease, neuropathic pain, intellectual disability, dementia, learning and memory ability deficiency and disorder syndrome, mental disorder, autism, schizophrenia, etc.
  • pharmaceutically acceptable carriers include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral administration (such as by injection or infusion).
  • the active compound i.e., the polypeptide of the present invention
  • the polypeptide/fusion polypeptide or pharmaceutical composition of the present invention can be administered by one or more routes of administration using one or more methods known in the art. It will be appreciated by those skilled in the art that routes of administration and/or modes vary depending on the desired results. Preferred routes of administration of the polypeptide/fusion polypeptide of the present invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, such as injection or infusion. Preferably, the polypeptide/fusion polypeptide of the present invention is administered by injection.
  • the dosage range can be about 0.000125 to 100 mg/kg, more typically 0.01 to 20 mg/kg recipient body weight.
  • the dosage can be 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight, 10 mg/kg body weight or 20 mg/kg body weight, or within the range of 1-20 mg/kg body weight.
  • an exemplary treatment regimen can be administered once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months, once every 3-6 months, or the initial administration interval is slightly shorter (such as once a day to 7 times every three weeks) and the later administration interval is lengthened (such as once a month to once every 3-6 months).
  • the specific administration regimen can be determined by a physician according to the patient's specific symptoms.
  • Example 1 Plasma degradation experiment without tPA and modification strategy
  • the amino acid sequence of the PMS-001 polypeptide is: Y 1 G 2 R 3 K 4 K 5 R 6 R 7 Q 8 R 9 R 10 R 11 Y 12 K 13 E 14 G 15 Y 16 N 17 V 18 Y 19 G 20 (SEQ ID NO: 29), wherein the superscript numbers of the amino acids indicate their amino acid position numbers.
  • the PMS-001 polypeptide consists of a Tat polypeptide (YGRKKRRQRRR, SEQ ID NO: 30) and a polypeptide of interest (YKEGYNVYG, SEQ ID NO: 2).
  • Tat transmembrane peptide is used in the development of many drug molecules.
  • the reported method to extend the half-life is to replace all L-amino groups in the Tat sequence with D-amino acids, thereby improving the stability of the product.
  • naturally occurring amino acids are generally L-amino acids, and D-amino acids in the human body are limited to a few types such as serine, the large-scale introduction of D-amino acids poses certain safety risks to the normal metabolism of amino acids and the execution of normal protein functions. Therefore, it is expected to minimize the introduction of D-amino acids.
  • Truncated variants of Tat polypeptides such as GRKKRRQRRR (SEQ ID NO: 31), or reverse variants such as RRRQRRKKRG (SEQ ID NO: 32) or RRRQRRKKRGY (SEQ ID NO: 33) can retain their ability to cross the blood-brain barrier and permeate cell membranes.
  • the present invention first studied the key amino acids that affect sequence stability, and carried out rat and human plasma degradation experiments to analyze the potential degradation sites of the product.
  • the degradation sites of the product PMS-001 include Y1, R3, K4, K5, R6, R7, Q8, R9, R10, R11, K13, etc.
  • Figure 1 mainly concentrated in Tat transmembrane peptides, and the in vitro half-life is short (Table 2).
  • the main sites of plasma metabolism were selectively modified according to the mass spectrometry analysis results of the PMS01-15-P plasma metabolism experiment, thereby designing PMS01-2-P (K5, R6, R7, R9, R10, R11, K13 amino acids replaced with corresponding D-amino acids) and PMS01-7-P (K5, R6, R7, R9, R10, R11 amino acids replaced with corresponding D-amino acids).
  • the results of this experiment also provide a model for the plasma stability modification of the transmembrane carrier Tat.
  • the combined modification of key sites not only reduces the number of D-type amino acid modifications, but also increases stability and safety, which can be used for other drug delivery.
  • Example 2 Plasma degradation experiment with tPA added and modification strategy
  • PMS01-2-P increases its stability by 30 times in plasma with tPA, although its half-life is similar to that of PMS01-7-P in plasma without tPA, indicating that the D-type modification of K13 is a key site in the presence of tPA.
  • the plasma degradation experiments under tPA conditions were further carried out on the previously modified products PMS01-3-P (R9, R10), PMS01-4-P (R9, R10, R11), PMS01-5-P (R9, R10, R11, K13), PMS01-6-P (R9, R10, K13), PMS01-8-P (R10, R11), PMS01-9-P (R10, R11, K13), and PMS01-10-P (R10). Since the D-type modification of the R and K sites of this series of peptides is further reduced, it is predicted that the stability under tPA conditions is poor.
  • K13 D-type amino acid was added to form new polypeptide molecules PMS01-24-P (K4, R7, R10, K13), PMS01-25-P (R3, R7, R10, K13), PMS01-26-P (R3, K5, R7, R10, K13) and PMS01-27-P (R3, R6, R10, K13).
  • the plasma stability test under tPA conditions was conducted on the newly designed peptide sequences above.
  • the main sites of this series of transformations are concentrated in the R site and K site, most of which are concentrated on the transmembrane peptide Tat.
  • the Tat sequence plays an important role in actual drug development, but due to its instability in plasma, the delivery effect is limited.
  • This study greatly improved the stability of Tat in plasma by D-type modification of specific amino acid combinations in the Tat sequence, while reducing the safety risk of D-type modification of the entire Tat sequence. Therefore, it is of great significance and provides a model for the plasma stability modification of the transmembrane carrier Tat.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
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Abstract

L'invention concerne une molécule active polypeptidique ayant une demi-vie prolongée et une stabilité améliorée, se rapportant au domaine de la biomédecine. La demi-vie et la stabilité de la molécule active polypeptidique sont augmentées au moyen du remplacement d'un acide aminé L à une position spécifique par un acide aminé D.
PCT/CN2024/084773 2023-03-31 2024-03-29 Molécule active polypeptidique ayant une demi-vie étendue et une stabilité améliorée Ceased WO2024199436A1 (fr)

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CN202480023870.2A CN120958011A (zh) 2023-03-31 2024-03-29 具有延长的半衰期和提高的稳定性的多肽活性分子

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060234912A1 (en) * 2003-10-08 2006-10-19 Wang Yu T Methods for modulating neuronal responses
US20100062985A1 (en) * 2008-09-03 2010-03-11 Arbor Vita Corporation Agents and methods for treating pain
WO2019006692A1 (fr) * 2017-07-05 2019-01-10 拜西欧斯（北京）生物技术有限公司 Composé pour traiter, atténuer ou prévenir une maladie liée au système nerveux et son utilisation
US20200385425A1 (en) * 2017-07-05 2020-12-10 Biocells (Beijing) Biotech Co., Ltd. Pharmaceutically acceptable salts of polypeptides and use thereof
CN115279797A (zh) * 2020-01-09 2022-11-01 诺诺公司 用于治疗中风和相关疾病的抗纤溶酶肽
CN115551531A (zh) * 2020-02-19 2022-12-30 诺诺公司 纤溶酶可裂解的psd-95抑制剂与再灌注联合治疗中风

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060234912A1 (en) * 2003-10-08 2006-10-19 Wang Yu T Methods for modulating neuronal responses
US20100062985A1 (en) * 2008-09-03 2010-03-11 Arbor Vita Corporation Agents and methods for treating pain
WO2019006692A1 (fr) * 2017-07-05 2019-01-10 拜西欧斯（北京）生物技术有限公司 Composé pour traiter, atténuer ou prévenir une maladie liée au système nerveux et son utilisation
US20200385425A1 (en) * 2017-07-05 2020-12-10 Biocells (Beijing) Biotech Co., Ltd. Pharmaceutically acceptable salts of polypeptides and use thereof
CN115279797A (zh) * 2020-01-09 2022-11-01 诺诺公司 用于治疗中风和相关疾病的抗纤溶酶肽
US20230055441A1 (en) * 2020-01-09 2023-02-23 Nono Inc. Plasmin-resistant peptides for treating stroke and related conditions
CN115551531A (zh) * 2020-02-19 2022-12-30 诺诺公司 纤溶酶可裂解的psd-95抑制剂与再灌注联合治疗中风

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