EP1003771A1 - Lineare peptidderivate von antibiotisch wirksamen peptiden, ihre herstellung und ihre verwendung um aktive substanzen auf ein ziel auszurichten - Google Patents

Lineare peptidderivate von antibiotisch wirksamen peptiden, ihre herstellung und ihre verwendung um aktive substanzen auf ein ziel auszurichten

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Publication number
EP1003771A1
EP1003771A1 EP98941556A EP98941556A EP1003771A1 EP 1003771 A1 EP1003771 A1 EP 1003771A1 EP 98941556 A EP98941556 A EP 98941556A EP 98941556 A EP98941556 A EP 98941556A EP 1003771 A1 EP1003771 A1 EP 1003771A1
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EP
European Patent Office
Prior art keywords
peptides
peptide
groups
antibiotic
linear peptide
Prior art date
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Ceased
Application number
EP98941556A
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English (en)
French (fr)
Inventor
Bernard Calas
Gérard Grassy
Alain Chavanieu
Michel Kaczorek
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Synt EM SA
Original Assignee
Synt EM SA
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Filing date
Publication date
Application filed by Synt EM SA filed Critical Synt EM SA
Publication of EP1003771A1 publication Critical patent/EP1003771A1/de
Ceased legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
    • A61K47/6897—Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies
    • A61K47/6898—Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies using avidin- or biotin-conjugated antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to linear peptides derived from antibiotic peptides and their use for vectorizing active substances. More particularly, the subject of the invention is new compounds formed from a linear derivative of an antibiotic peptide linked to at least one active substance, as well as the preparation of these compounds and the compositions containing them.
  • Antimicrobial peptides from vertebrates whatever their origin, lower or higher vertebrates, myeloid or non-myeloid tissues, have a number of common properties:
  • amphipathic structure is understood to mean structures in which the hydrophobic residues are spatially separated from the hydrophilic residues.
  • antibiotic peptides can be classified into three main families:
  • antibiotic peptides with destructured chains containing numerous bends linked to the presence of multiple prolines bactenecins and PR39 (Frank, R. W. et al., 1991, Eur. J. Biochem. 202, 849-
  • antibiotic peptides act by direct lysis of the membrane of pathogenic cells. Their basic nature facilitates their interaction with negatively charged phospholipids, and their amphipatic nature then allows them to be incorporated into the membrane where they aggregate to form pores through which the cell loses its substance. It is generally accepted that their preferential selectivity for prokaryotic cells is due to the particular composition of their membranes which contain more anionic phospholipids than those of eukaryotes. In addition, the plasma membranes of mammalian cells all contain cholesterol, the role of which is to modulate its fluidity. and which could hinder the incorporation of antibiotic peptides. However, the specificity of the latter for microorganisms is low so that they have a high cytotoxicity which limits their use.
  • antibiotic peptides are of considerable interest because of their broad spectrum of action and the difficulty that microorganisms have in implementing inactivation strategies. As a result, a great deal of research is undertaken to try to find new molecules and to obtain analogues which are more efficient than the parent peptides. In the future, these antibiotic peptides may be called upon to replace antibiotics from bacteria or fungi.
  • the PCT international patent applications published under the numbers O95 / 03325, WO96 / 37508 and WO97 / 02287 describe a new class of antibiotic peptides, designated "protectins", isolated from pig leukocytes or else prepared by chemical synthesis or by genetic engineering and exhibiting antibacterial, antiviral and antifungal activities.
  • Protinins are used to designate a set of five peptides designated PG-1, PG-2, PG-3, PG-4 and PG-5, the sequences of which are given below, closely related and isolated from pig leukocytes ( VN Kokryakov & col. FEBS lett. 327, 231-236):
  • Proteins, tachyplines and polyphemusins contain a high proportion of basic residues (lysines and arginines) and have four cysteines which form two parallel disulfide bridges. These three families of peptides also exhibit homologies with certain defensins and in particular with human defensin NP-1 (Kokryakov, V. N. et al., 1993, Febs Let. 327, 231-236).
  • Tachyplines and protectins have a similar three-dimensional structure. It is an antiparallel ⁇ sheet stabilized by the two disulfide bridges. These bridges play an important role in the antibacterial activity of protectins and tachyplesins. Their removal, either by protecting the SH groups with acetamidomethyls, or by replacing the cysteines with alanines or glycines, leads to analogs practically devoid of activity in vivo (Lehrer, RI et al., 1996, Eur. J. Biochem. 240: 352-357).
  • the protectins and the tachyplesins have an important lytic activity on the prokaryotic cells.
  • the research carried out by the Applicant on the cytotoxicity of these peptides on cultured mammalian cells has made it possible to demonstrate, before the death of the cells, non-negligible amounts of protectins and tachyplesins in the cytoplasm of said cells. . It has been envisaged that the presence of peptides in the cytoplasm could result from transport through pores, but these pores are only permeable to ions and small molecules and their diameter is too small to allow the passage of peptides. antibiotics. It would seem that the proteines and tachyplines, in addition to puncturing the plasma membrane, are able to cross it.
  • vectorization system a process capable of transporting said active substance to a target, such as for example:
  • the subject of the present invention is therefore peptides derived from antibiotic peptides or analogs thereof, characterized in that they are devoid of the disulfide bridge.
  • analog Pept ides antibiotic, a peptide whose amino acid sequence has been modi f ied without this n 'enta viable modif ication in the antibiotic properties of said peptide.
  • the above modifications advantageously relate to all the cysteine residues of the antibiotic peptide, but as soon as the presence of a single cysteine residue does not allow the formation of a disulfide bridge, the peptides of the invention can contain a single cysteine.
  • Natural antibiotic peptides generally have 4 or 6 cysteine residues capable of forming two or three disulfide bridges, also in the peptides of the invention, only one of these cysteines can be maintained and the other three or five are modified or blocked .
  • the antibiotic peptides from which the peptides of the invention are derived may be defensins, protectins, tachyplesins or their analogs, the antibiotic properties of which are imparted to them by their tertiary structure resulting from the presence of disulfide bridges.
  • Linear peptides according to the invention correspond to one of the following formulas:
  • BBXXXBXXXBXXXXBBXB (II) which can also be represented by the following unique formula (III): B (XB) X (XB) X (XB) XX (XB) B (XB) XXX (XB) (XB) XB in which:
  • - groups B identical or different, represent an amino acid residue whose side chain carries a basic group
  • - groups X identical or different, represent an aliphatic or aromatic amino acid residue, or consist of '' a sequence of at least
  • B and X can be natural amino acids or not, including amino acids of configuration D.
  • B and X can be cited: - B is chosen from arginine, lysine, diaminoacetic acid, diaminobutyric acid, 1 diaminopropionic acid, 1 ornithine.
  • - X is chosen from glycine, alanine, valine, norleucine, isoleucine, leucine, cysteine, cysteine, penicillamine, methionine, serine, threonine, 1 asparagine, glutamine, phenylalanine, histidine, tryptophan, tyrosine, proline, Abu, amino-1-cyclohexane carboxylic acid, Aib, 2-aminotetraline carboxylic, 4-bromophenylalanine, tert-Leucine, 4-chlorophenylalanine, ⁇ -cyclohexylalanine, 3, 4-dichlorophenylalanine, 4-fluorophenylalanine, 1 homoleucine, ⁇ -homoleucine,
  • the invention also relates to derivatives of the peptides of formulas (I) or (II) such as said peptides in retro form, or fragments of the peptides of formulas (I) or (II) consisting of five and preferably seven successive amino acids of one of the formulas (I) or (II).
  • derivatives of the peptides of formulas (I) or (II) such as said peptides in retro form, or fragments of the peptides of formulas (I) or (II) consisting of five and preferably seven successive amino acids of one of the formulas (I) or (II).
  • groups X represent a natural or unnatural amino acid (including amino acids of configuration D) aliphatic or aromatic, such as glycine, alanine, valine, norleucine, isoleucine, leucine, cysteine , the
  • ⁇ rjrn cysteine penic il lamine, methionine, serine, threonine, asparagine, glutamine, phenylalanine, histidine, tryptophan, tyrosine, proline, 1 'bu, amino-1 acid -carboxylic cyclohexane, Aib, carboxylic 2-aminotetralin, 4-bromophenylalanine, tert-Leucine, 4-chlorophenylalanine, ⁇ -cyclohexylalanine, 3,4-dichlorophenylalanine, 4-f luorophenylalanine, 1 'homo leuc , ⁇ -homo leucine, 1 homophenylalanine,
  • B represents Napthylalanine
  • O represents Ornithine
  • X represents Norleucine
  • Z represents Norvaline.
  • the invention also relates to the use of the above peptides for the vectorization of one or more active substances both for therapeutic and diagnostic applications.
  • active substance the invention envisages in particular proteins or protein fragments, such as polypeptides or peptides, antibodies or part of antibodies, nucleic acids and oligonucleotides or ribozymes, or, of course, active chemical molecules for the treatment or prevention of human or animal pathologies, such as, for example and without limitation, anti-tumor agents , antivirals, anti-inflammatory agents, agents preventing the degradation of organs and / or tissues, etc.
  • the active substance can be a radioactive marker, a colored marker, or any other means or substance capable of revealing a metabolism or a pathology.
  • the invention therefore also relates to compounds of formula (IV) below, as well as the compositions containing them:
  • - Y represents a signal agent
  • - n is 0 and or more, and advantageously 0 or 1
  • - m is 1 or more, and preferably up to 10 advantageously up to 5.
  • the compounds of formula (IV) above are formed from a peptide of the invention coupled to one or more active substances, identical or different, represented by the group (Z) in the formula (IV), and optionally one or more signal agents, represented by the group (Y) in formula (IV), having a role of addressing the compound of formula
  • the signal agent (Y) is an oligopeptide or a protein, such as a signal peptide, a nuclear localization signal, an antibody fragment, or a chemical molecule ligand or anti-ligand of a receptor.
  • the group (Y) is attached to the group (Z).
  • the coupling symbolized by the horizontal lines in the formula (IV), can be carried out by any acceptable means of connection taking into account the chemical nature, the bulk and the number of groups (Z) and (Y) in the compounds of formula (IV), such as covalent, hydrophobic or ionic bonds, cleavable or non-cleavable in physiological media.
  • the coupling can be carried out at any site of the peptide (A), in which functional groups such as -OH, -SH, -COOH, -NH2 are naturally present or have been introduced.
  • the invention also envisages the attachment of several groups (Z) to the same site of the peptide (A), either directly, if this site comprises several functional groups, as in the case of a C- or N-terminal lysine, either indirectly via an intermediate group carrying several reaction groups making it possible to fix therein several groups (Z).
  • the preferred coupling positions for the active substance are at the N-terminal or C-terminal ends or else at the level of the primary amino groups carried by the side chains of the lysines of peptide (A).
  • the N-terminal end of the peptide (A) is used to hook the active substance (Z)
  • the N-terminal end is available for possible coupling to a signal agent (Y) allowing the addressing the compound of the invention either towards the nucleus, or even towards a particular tissue type.
  • the covalent peptide-drug complex after administration is distributed in the cytoplasm of the target cell. It is possible to bring this complex into the nuclear compartment by coupling to the N-terminal end of the peptide a short basic sequence, for example of about 7 amino acids, corresponding to a nuclear localization signal. Under these conditions, biotin or doxorubicin is found in the nucleus of the cell.
  • the pentadecapeptide 0CM2 (Swolapenko, GB et al., 1995, The Lancet 346, 1662-65) synthetic, fragment of a monoclonal antibody, directed against an antigen expressed by breast cancer cells (Tumor Associated Antigen Polymorphic Epithelial Mucin), retains a good affinity for these cells. It is therefore possible, by combining aM2 with a linear peptide-drug set, to bring this set preferentially towards the cells which express the antigenic characteristic linked to breast cancer.
  • the compounds of formula (IV) can be prepared by chemical synthesis or by using molecular biology techniques. It is possible to use for chemical synthesis commercial devices making it possible to incorporate non-natural amino acids, such as the D enantiomers and residues having side chains having hydrophobicities and bulkings different from those of their natural counterparts. During the synthesis, it is obviously possible to make a wide range of modifications, for example introducing a lipid (prenyl or myristyl) onto the N-terminal so as to be able to anchor the peptide of the invention and therefore the compound of formula (IV) to a lipid membrane such as that of a liposome consisting of positively charged lipids.
  • a lipid prenyl or myristyl
  • the present invention also relates to a nucleic acid molecule comprising or consisting of a nucleic sequence coding for a linear peptide derived from antibiotic peptide. More particularly the invention relates to a nucleic acid molecule comprising at least one sequence coding for a compound of formula (IV) or part of that of a protein nature.
  • These nucleic acid sequences can be DNA or RNA and be associated with control sequences and / or be inserted into vectors. The vector used is chosen according to the host to which it will be transferred; it can be any vector such as a plasmid.
  • nucleic acids and vectors are useful for producing linear peptides and compounds of formula (IV) or part of them of a protein nature in a cellular host.
  • such a process for producing a peptide according to the invention consists in: transferring a nucleic acid molecule or a vector containing said molecule to a cellular host,
  • the cell host used in this type of process can be chosen from prokaryotes or eukaryotes and in particular from bacteria, yeasts, mammalian, plant or insect cells.
  • the invention therefore also relates to the transformed cells expressing the linear peptides or the compounds of formula (IV) or part of these of a protein nature.
  • the invention also relates to: pharmaceutical compositions comprising as active principle at least one compound of formula (IV) optionally associated with an acceptable vehicle or support.
  • Example 1 Binding of biotin and doxorubic ine on linear analogues of antibiotic peptides.
  • RGGRLCYCRRRFCVCVGR-NH2 tachyplesin 1 of formula: KWCFRVCYRGICYRRCR-NH2, polyphemusine of formula:
  • These three peptides can be prepared either from a BOC chemistry or from a FMOC chemistry, by conventional methods of synthesis in solid or homogeneous phase.
  • the peptide After cleavage of the purification support, the peptide is treated with glutaric anhydride in the presence of triethylamine. The peptide is then purified and the -COOH group carried by the glutaryl at the N-terminal is activated by the mixture of diisopropylcarbodiimide and 1-hydroxybenzotriazole. After two hours of reaction at room temperature, doxorubicin is added and the mixture is stirred for 12 hours at 0 ° C. The whole pept ide-doxorubic ine is then purified by high pressure liquid chromatography.
  • Example 2 Ability of linear peptides of the invention to pass cell membranes.
  • the ability of peptides to pass membranes has been tested on various cell types (MCF7, MCF7R, HL60, HL60R, HeLa).
  • the cells are cultured on RPMI 1640
  • the cells are incubated in Opti-Mem (Gibco) for one hour before being treated for variable times with the peptides labeled with biotin.
  • Example 1 The latter are obtained in accordance with Example 1 (2) by treating 1 equivalent of linear peptide with 2 equivalents of N-hydroxysuccinimide ester of biotin, then purified by high pressure liquid chromatography.
  • the cells are then fixed with a 3.7% paraformaldehyde solution for 5 minutes at
  • the cells are incubated for 15 minutes, then rinsed with PBS and then the doxorubicin present in the cell is determined by chromatography.
  • - U represents serine or threonine
  • - R represents arginine
  • groups X represent a natural or unnatural amino acid (including amino acids of configuration D) aliphatic or aromatic, such as glycine, alanine, valine, norleucine, isoleucine, leucine, cysteine , the
  • .A.cm cysteine penicillamine, methionine, serine, threonine, asparagine, glutamine, phenylalanine, histidine, tryptophan, tyrosine, proline, 1 'Abu, amino acid 1-cyclohexane carboxylic, Aib, 2-aminotetralin carboxylic, 4-bromophenylalanine, tert-Leucine, 4-chlorophenylalanine, ⁇ -cyclohexylalanine, 3,4-dichlorophenylalanine, 4 -fluorophenylalanine, 1 'homoleucine ⁇ -homoleucine, 1 homophenylalanine,
  • biotin alone does not enter the cell and accumulates weakly around it.
  • biotin is rapidly entrained by the linear peptide of the invention inside the cell where it is present in the cytoplasm and in the nucleus of the cell .
  • Example 3 Capacity for internalization of the linear peptides of the invention.
  • Linear peptides of the invention derived from Proteins and Tachyplesins were tested on different cell lines, with the aim of evaluating their respective internalization.
  • the cells are seeded at approximately 10 cells per well, 24 h before the addition of the biotinylated peptides. They are then at 60-80% confluence on the day of the experiment.
  • the biotinylated peptides are incubated with the cells at a concentration of 10 ⁇ M, for 15 minutes, at 37 ° C. in an atmosphere at 95% humidity and 5% CO 2 in an OptiMem medium.
  • the cells are washed three times with PBS at room temperature and then are fixed with formalin (3.7% formaldehyde in PBS, 10 min at room temperature). They are then washed with PBS and permeabilized for 15 min with PBS-TritonX-100.
  • the cell nuclei were stained with Hoechst.
  • Non-tumor lines MRC5 (lung fibroblast), HuVeC (endothelial, umbilical cord).
  • Tumor lines HT29 (colon carcinoma), HepG2 (hepatoblastoma), A172 (glioblastoma), HMCB (elanoma).
  • the cells are cultured at 37 ° C. in an atmosphere at 95% humidity and 5% CO 2.
  • the culture medium is that recommended by the ATCC.
  • FIGS. 1 and 2 The fluorescence microscopy photos of the internalization are presented in FIGS. 1 and 2.
  • the peptide SM 1738 presented by way of example, appears to be located mainly in the cytoplasm and in a perinuclear zone.
  • the peptide has a localization mainly cytoplasmic.
  • the left column corresponds to the coloring of the nucleus by Hoechst.
  • the internal i sat ion photos are shown in Figures 3 and 4 in the appendix.
  • the biotinylated peptide is localized in the cytoplasm in a diffuse fashion and also clearly marks nuc leole.
  • the left column corresponds to the coloring of the nucleus by Hoechst.
  • the cells are seeded at approximately 10 cells per well, 24 h before the addition of the products. They are then at 60-80% confluence on the day of the experiment.
  • Free doxorubicin on the one hand, or doxorubicin coupled to the vector SM1738 on the other hand are incubated with MCF7 cells at a concentration of 10 ⁇ M, for 60 minutes, at 37 ° C. in an atmosphere at 95% humidity. and 5% CO 2 in the culture medium.
  • the subcellular localization of the naturally fluorescent doxorubicin was determined by confocal microscopy. The results are presented in Figure 5 in the appendix. Localization is partly cytoplasmic and partly nuclear. The nucleus is then diffusedly marked.
  • amino acids are represented by their one-letter code, but they can also be represented by their three-letter code according to the nomenclature below.

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EP98941556A 1997-08-12 1998-08-06 Lineare peptidderivate von antibiotisch wirksamen peptiden, ihre herstellung und ihre verwendung um aktive substanzen auf ein ziel auszurichten Ceased EP1003771A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9710297A FR2767323B1 (fr) 1997-08-12 1997-08-12 Peptides lineaires derives de peptides antibiotiques, leur preparation et leur utilisation pour vectoriser des substances actives
FR9710297 1997-08-12
PCT/FR1998/001757 WO1999007728A2 (fr) 1997-08-12 1998-08-06 Peptides lineaires derives de peptides antibiotiques, leur preparation et leur utilisation pour vectoriser des substances actives

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EP1003771A1 true EP1003771A1 (de) 2000-05-31

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EP98941556A Ceased EP1003771A1 (de) 1997-08-12 1998-08-06 Lineare peptidderivate von antibiotisch wirksamen peptiden, ihre herstellung und ihre verwendung um aktive substanzen auf ein ziel auszurichten

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EP (1) EP1003771A1 (de)
JP (1) JP2001512739A (de)
AU (1) AU754617B2 (de)
CA (1) CA2298932A1 (de)
FR (1) FR2767323B1 (de)
IL (1) IL134293A0 (de)
WO (1) WO1999007728A2 (de)

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CA2388991A1 (en) * 1998-11-11 2001-04-19 Peter E. Nielsen Conjugates between a peptides and a nucleic acid analog, such as a pna, lna or a morpholino
DK173006B1 (da) * 1998-11-11 1999-11-01 Ke Burgmann As Fremgangsmåde og anlæg til frembringelse af vægmateriale til brug ved fremstilling af kompensatorer, navnlig til røggaskanaler, samt kompensatormateriale og kompensator frembragt ved fremgangsmåden
FR2786398B1 (fr) * 1998-11-30 2002-12-27 Synt Em Composition pharmaceutique anti-cancereuse et anti-chimioresistance comprenant un agent anticancereux et au moins un peptide
FR2786397B1 (fr) * 1998-11-30 2003-01-10 Synt Em Vecteurs peptidiques de substances a travers la barriere hematoencephalique pour etre utilises dans le diagnostic ou la therapie d'une affection du snc
US8183339B1 (en) 1999-10-12 2012-05-22 Xigen S.A. Cell-permeable peptide inhibitors of the JNK signal transduction pathway
US20040082509A1 (en) 1999-10-12 2004-04-29 Christophe Bonny Cell-permeable peptide inhibitors of the JNK signal transduction pathway
FR2810985B1 (fr) * 2000-07-03 2004-12-24 Synt Em Peptides lineaires amphipathiques et les compositions les contenant
GB0103110D0 (en) 2000-08-25 2001-03-28 Aventis Pharma Inc A membrane penetrating peptide encoded by a nuclear localization sequence from human period 1
US7033597B2 (en) * 2000-10-13 2006-04-25 Université de Lausanne Intracellular delivery of biological effectors
US7034109B2 (en) * 2000-10-13 2006-04-25 Christophe Bonny Intracellular delivery of biological effectors
FR2821272B1 (fr) * 2001-02-23 2004-12-17 Synt Em Composes constitues d'une molecule analgesique liee a un vecteur capable de vectoriser ladite molecule a travers la barriere hematoencephalique et compositions pharmaceutiques les contenant
FR2829940A1 (fr) * 2001-09-27 2003-03-28 Synt Em Compositions pour la vectorisation d'anticorps a travers la barriere hematoencephalique et leur utilisation pour le diagnostic ou le traitement des maladies du systeme nerveux central
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FR2767323B1 (fr) 2001-01-05
AU8988998A (en) 1999-03-01
WO1999007728A2 (fr) 1999-02-18
AU754617B2 (en) 2002-11-21
IL134293A0 (en) 2001-04-30
WO1999007728A3 (fr) 1999-06-24
JP2001512739A (ja) 2001-08-28
FR2767323A1 (fr) 1999-02-19
CA2298932A1 (fr) 1999-02-18

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