WO2007022534A1 - Preparation d'un compose peptidique (norapro-2002) et son utilisation dans l'activation d'enzymes proteines phosphatases-2a - Google Patents

Preparation d'un compose peptidique (norapro-2002) et son utilisation dans l'activation d'enzymes proteines phosphatases-2a Download PDF

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Publication number
WO2007022534A1
WO2007022534A1 PCT/US2006/032723 US2006032723W WO2007022534A1 WO 2007022534 A1 WO2007022534 A1 WO 2007022534A1 US 2006032723 W US2006032723 W US 2006032723W WO 2007022534 A1 WO2007022534 A1 WO 2007022534A1
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Prior art keywords
protein phosphatase
peptide
norapro
cell
activator
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PCT/US2006/032723
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English (en)
Inventor
Hin Young Lim Tung
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Propepgen Biostrategies, Inc.
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Priority to PCT/US2006/032723 priority Critical patent/WO2007022534A1/fr
Publication of WO2007022534A1 publication Critical patent/WO2007022534A1/fr

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    • 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

  • Protein phosphatase-2A enzymes are key enzymes of the protein phosphorylation/dephosphorylation of the cell (Ingebritsen 1983; Cohen 1989; Jannssens 2001).
  • One form of protein phosphatase-2A termed protein phosphatase- 2A 1 is involved in the dephosphorylation of proteins that are important for the control of cell maintenance, cell proliferation and cell death (Tung 1984; Tung 1985; Meijer 1986;. Deng 1998; Chiang 2002; Chiang 2003). It has a basal activity in the cell that is necessary for cell maintenance (Ingebritsen 1983; Ingebritsen 1983).
  • Low activity of protein phosphatase-2Al is associated with proliferation while high activity is associated with cell death (Millward 1999; Petritsch 2000; Li 2001; Garcia 2003; Morrow 2004; Janoo 2005).
  • Activating molecules of protein phosphatase-2Al will be useful in inhibiting cell proliferation and induction of death of cancer cells.
  • HIV-I Vpr may be an activator of protein phosphatase-2Al (Emerman 1996; Tung 1997). However, full length HIV-I Vpr was tested and it was shown not to activate protein phosphatase- 2AI (Tung 1997; Janoo 2005). Analysis of the C-terminal fragment of HIV-I Vpr indicates that the C-terminal fragment of HIV-I Vpr may be an activator of protein phosphatase-2Al .
  • FIG. 1. shows the structure of the peptide compound (NORAPRO-2002) that was synthesized and that acts as a weak activator of protein phosphatase-2Al .
  • FIG. 2. shows the activation of protein phosphatase-2Al by various concentrations of SYRAPRO-2000 and NORAPRO-2002.
  • SYRAPRO-2000 activates protein phosphatase-2Al by 700% whereas NORAPRO-2002 activates protein phosphatase- 2Al by only 200%.
  • FIG. 3. shows that NORAPRO-2002 causes activation of protein phosphatase-2A enzymes in intact cells.
  • the instant invention provides peptides designated NORAPRO (SEQ ID NO: 1) for the modulation of protein phosphatase 2Al , e.g., the weak activation of protein phosphatase 2Al .
  • the instant invention provides peptides comprising SEQ ID NO: 1.
  • the instant invention provides peptides consisting of the sequence set forth as SEQ ID NO: 1.
  • the peptides can be made synthetically or by expression in recombinant host cells.
  • the invention provides peptide activators of protein phosphatase-2Al , comprising the sequence TRQRRAR (SEQ ID NO:2).
  • the invention provides peptide activators of protein phosphatase-2Al comprising an N-amino acid sequence HSRIGV (SEQ ID NO:3).
  • the peptides are at 10-30 amino acids in length, 15-25 amino acids in length, 18-22 amino acids in length, or about 20 amino acids in length.
  • the invention provides a peptide activator of protein phosphatase 2Al comprising the amino acid sequence HSRIGVTRQRRARNGASRS (SEQ ID NO:1).
  • the peptides of the instant invention can be used to treat diseases and disorders in which activation of protein phosphatase 2Al, e.g., weak activation, would be beneficial.
  • Exemplary diseases and disorders include cancer, e.g., brain cancer, and neurodegenerative diseases, e.g., Alzheimer's disease.
  • the peptides of the invention are useful for the differentiation of stem cells.
  • the peptide activators of the invention can be conjugated to one or more therapeutic or diagnostic moieties.
  • the peptides can be conjugated to a chemotherapeutic, a radiolabel, or the like for the purposes of treatment or diagnosis of a condition.
  • the present invention also provides for the administration of the peptides of the invention in a suitable pharmaceutical formulation.
  • administration or administering is meant providing one or more peptides or peptide-containing compositions of the invention as a drug, prodrug, or a drug-metabolite, to an individual in need of treatment or prevention of a cell proliferative disorder.
  • a drug which contains one or more of the peptides and/or peptide containing compositions of the present invention, as the principal or member active ingredient, for use in the treatment or prevention of a cell proliferative disorder, e.g., cancer can be administered in a wide variety of therapeutic dosage forms in the conventional vehicles for topical, oral, systemic, local, and parenteral administration.
  • compositions for parenteral administration which comprise a solution of the peptides dissolved or suspended in an acceptable carrier, preferably an aqueous carrier.
  • an acceptable carrier preferably an aqueous carrier.
  • aqueous carriers may be used, e.g., water, buffered water, 0.4% saline, 0.3% glycine, hyaluronic acid and the like.
  • These compositions may be sterilized by conventional, well known sterilization techniques, or may be sterile filtered.
  • the resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration.
  • compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, among many others.
  • auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, among many others.
  • auxiliary substances such as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, among many others.
  • the route and regimen of administration will vary depending upon the stage or severity of the cell proliferative disorder, e.g., cancer, to be treated, and is to be determined by the skilled practitioner.
  • the peptides and peptide- containing compositions can be administered in such oral dosage forms for example as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection.
  • they may also be administered in intravenous (either by bolus or infusion methods), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form.
  • the peptides and peptide-containing compositions are administered intradermally or subcutaneously. All of these forms are well known to those of ordinary skill in the pharmaceutical arts.
  • the daily dose of the peptides and compositions of the invention may be varied over a range from 0.001 to 1,000 mg per adult per day.
  • the compositions are preferably provided in the form of tables containing from 0.001 to 1,000 mg, preferably 0.001, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 10.0, 20.0, 50.0, 100.0 milligrams of active ingredient for the symptomatic adjustment of dosage according to signs and symptoms of the patient in the course of treatment.
  • An effective amount of drug is ordinarily supplied at a dosage level of from about 0.0001 mg/kg to about 50 mg/kg of body weight per day. The range is more particular from about 0.0001 mg/kg to 7 mg/kg of body weight per day.
  • suitable formulations of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses for example of two, three, or four times daily.
  • the peptides and compositions of the present invention may be used to prepare a medicament or agent useful for the treatment of the cell proliferative disorder, .
  • compounds of the present invention can be administered in intranasal form, or via transdermal routes known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regimen.
  • the peptides of the present invention may be administered in a pharmaceutical composition comprising the active compound in combination with a pharmaceutically acceptable carried adopted for topical administration.
  • Topical pharmaceutical compositions may be, for example, in the form of a solution, cream, ointment, gel, lotion, shampoo, or aerosol formulation adapted for application to the skin.
  • These topical pharmaceutical composition containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle.
  • compositions of the present invention may be used together with other agents known to be useful in treating such malignancies.
  • the active agents can be administered concurrently, the active agents can be administered concurrently, or they can be administered separately at staggered times.
  • the dosage regimen utilizing the compositions of the present invention is selected in accordance with a variety of factors, including for example type, species, age, weight, sex and medical condition of the patient, the stage and severity of the cell proliferative disorder and the particular compound thereof employed.
  • a physician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the malignancy.
  • Optimal precision in achieving concentration of drug with the range that yields efficacy either without toxicity or with acceptable toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This process involves a consideration of the distribution, equilibrium, and elimination of the drug, and is within the ability of the skilled practitioner.
  • the peptides herein described in detail can form the active ingredient and are typically administered in admixture with suitable pharmaceutical diluents or excipients suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups, and the like, and consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents or excipients suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, aga, bentonite, xanthan gum and the like.
  • the liquid forms may be suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl cellulose and the like.
  • Other dispersing agents which may be employed are glycerin and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • Topical preparations containing the active drug component can be admixed with a variety of carrier materials well known in the art, such- as, for example, alcohols, aloe vera gel, allatoin, glycerine, vitamins A or E oil, mineral oil, PPG2 myristyl propionate, and the like, to form, for example, alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations.
  • carrier materials well known in the art, such- as, for example, alcohols, aloe vera gel, allatoin, glycerine, vitamins A or E oil, mineral oil, PPG2 myristyl propionate, and the like, to form, for example, alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations.
  • the peptides or formulation thereof of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihyrdo-pyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihyrdo-pyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • subjects can receive an intradermal injection of an effective amount of the peptides either in combination with delivery vectors, such as virosomes, or by themselves.
  • the peptides of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilameller vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of compounds, including for example cholesterol, stearylamine, and various phosphatidylcholines.
  • Immune response potentiating compounds are classified as either adjuvants or cytokines.
  • Adjuvants may enhance the immunological response by providing a reservoir of antigen (extracellularly or within macrophages), activating macrophages and stimulating specific sets of lymphocytes.
  • Adjuvants of many kinds are well known in the art; specific examples include Freund's, alum, mycobacteria such as BCG and M.
  • Cytokines are also useful in vaccination protocols as a result of lymphocyte stimulatory properties. Many cytokines useful for such purposes will be known to one of ordinary skill in the art, including interleukin-2 (IL-2), IL-I 2, GM-CSF and many others.
  • IL-2 interleukin-2
  • IL-I 2 IL-I 2
  • GM-CSF GM-CSF
  • the therapeutic compositions of the present invention are administered in pharmaceutically acceptable preparations. Such preparations may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, supplementary immune potentiating agents such as adjuvants and cytokines and optionally other therapeutic agents.
  • the preparations of the invention are administered in effective amounts.
  • An effective amount is that amount of a pharmaceutical preparation that alone, or together with further doses, stimulates the desired response.
  • doses of immunogens ranging from one nanogram/kilogram to 100 miligrams/kilogram, depending upon the mode of administration, are considered effective:
  • the preferred range is believed to be between 500 nanograms and 500 micrograms per kilogram.
  • the absolute amount will depend upon a variety of factors, including the composition selected for administration, whether the administration is in single or multiple doses, and individual patient parameters including age, physical condition, size, weight, and the stage of the disease. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation.
  • the desired response is inhibiting the progression of the cancer and/or inducing the regression of the cancer and its metastases. These desired responses can be monitored by routine methods.
  • the invention also provides methods for producing large quantities of undifferentiated stem cells.
  • the invention provides a method for enhancing the proliferation of stem cells by contacting a stem cell, e.g., an undifferentiated stem cell, with a peptide of the invention, thereby enhancing the proliferation of the stem cell.
  • This invention relates to the preparation of a peptide compound (Norapro-
  • NORAPRO-2002 The peptide compound (NORAPRO-2002), was designed based on the assumption that it is would act as a weak activator of protein phosphatase-2Al .
  • the structure of NORAPRO-2002 is HSRIGVTRQRRARNGASRS (SEQ ID NO:1).
  • NORAPRO-2002 can be synthesized on an automated Solid Phase Peptide Synthesizer and the synthesized compound can activate purified protein phosphatase-2Al in vitro by -200%.
  • NORAPRO-2002 was designed as a weak activator of protein phosphatase-2Al because it is desirable to activate protein phosphatase-2A enzymes in intact cells.
  • the effect of synthesized NORAPRO-2000 on the activity of protein phosphatase-2A enzymes can be determined in intact cells.
  • Jurkat cells, a human CD 4+ T cell line are grown in RPMI 1640 and DMEM supplemented with 10% (v/v) fetal bovine serum and antibiotics and treated or not with 100 uM of hours.
  • cells are harvested and cell extracts are prepared by homogenization and centrifugation.
  • the activities of protein phosphatase-2A enzymes are then determined following chromatography on DEAE Sepharose. It can be shown that NORAPRO-2002 causes the activation of protein phosphatase-2A enzymes by - 180%.
  • 32 P-labeled phosphorylase a was prepared by phosphorylation of phosphorylase b with phosphorylase kinase as described in (Cohen 1988).
  • 32 P-labeled casein was prepared by phosphorylation of casein with protein kinase A as described in (Tung 1986).
  • Strong peptide activator compound of protein phosphatase-2Al (SYRAPRO-2000) and weak peptide activator compound of protein phosphatase-2Al were prepared by chemical synthesis on an automated Solid Phase Peptide Synthesizer and purified as described in (Azzi 1992).
  • the molecular mass of the peptide activator compounds of protein phosphatase-2Al were confirmed by MALDI ToF MS.
  • the sequence SYRAPRO-2000 is HFRIGCRHSRIGVTRQRRARNGASRS (SEQ ID NO:4) and the sequence of NORAPRO-2002 is HSRIGVTRQRRARNGASRS (SEQ ID NO:1).
  • the assay of protein phosphatases-2Ai consisted of 0.02 ml of enzyme solution in 50 mM Imidazole-Cl pH 7.2, 0.2 mM EGTA, 0.1 % (v/v) 2-mercaptoethanol and 1 mg/ml bovine serum albumin (Assay Buffer), 0.01 ml of inhibitor-2 at 600 nM in Assay Buffer, 0.01 ml of protamine at 60 mg/ml in Assay Buffer or 0.01 ml of SYRAPRO- 2000 or NORAPRO-2002 at different concentrations in Assay Buffer or 0.01 ml of Assay Buffer alone, 0.02 ml of 32 P-labeled phosphorylase at 3 mg/ml in Assay Buffer containing 15 mM caffeine.
  • the assay components were preincubated for 10 minutes prior to initiating the reaction with 32 P-labeled phosphorylase A.
  • One unit of protein phosphatase activity is that amount of enzyme which catalyzes the release of 1 nmol of phosphate from 32 P-labeled substrate per min at 30° C.
  • Jurkat cells a human transformed CD 4+ T cell line, were grown in grown in RPMI 1680 supplemented with 5% (v/v) fetal bovine serum at 37° C in 95% air/5% CO 2 in a humidified incubator. 2.4 liters of cells were collected by centrifugation at 4200 rpm in a low speed centrifuge for 10 minutes.
  • the cells were homogenized in 80 ml of 50 mM Imidazole-Cl pH 7.2, 2 mM EGTA, 2 niM EDTA, 0.1% (v/v) 2- mercaptoethanol, 0.2 mM PMSF, 1 mM benzamidine, 4ug/ml aprotinin, 4 ug/ml leupeptin, , 4 ug/ml pepstatin, 0.1 mM TLCK, 0.1 mM TPCK, 1 mM sodium orthovanadate and 10% (v/v) glycerol by 40 strokes in a glass hand held homogenizer.
  • the homogenate was centrifuged at 29000 rpm in a high speed centrifuge for 30 minutes.
  • the supernatant i.e. the extract
  • the supernatant was collected and loaded onto a DEAE Sepharose column (1.5 x 6 cm) equilibrated in 25 mM Imidazole-Cl pH 7.2, 0.2 mM EGTA, 0.1 % (v/v) 2- mercaptoethanol, 0.1 mM PMSF, 1 mM benzamidine and 10% (v/v) glycerol (Buffer A).
  • the column was washed with 50 ml of Buffer and then eluted with a 200 ml linear gradient of Buffer A to Buffer A plus 0.4 M NaCl.
  • the eluted fractions were then assayed for phosphorylase phosphatase activity in the presence of 100 nM inhibitor-2 and 10 ⁇ g/ml of protamine. Two major peaks of phosphorylase phosphatase were observed. The first and second peak represent protein phosphatase-2Ao and protein phosphatase-2Ai respectively. The second peak eluting at around 0.2 M NaCl, representing the largest proportion of the total protein phosphatase activity and which became activated following treatment OfCD 4+ T cells with HIV-I Vpr 71"96 (Fig.
  • the column was washed with 50 ml of Buffer A and then eluted with a 200 ml linear gradient of Buffer A to Buffer A plus 0.5 M NaCl.
  • the active fractions eluting at ⁇ 0.30 M NaCl salt concentration was pooled, concentrated by vacuum dialysis and stored at -20 0 C in 50 mM Imidazole-Cl pH 7.2, 0.2 mM EGTA in the presence of 50% (v/v) glycerol.
  • the highly purified enzyme consisted of the characteristic subunits of protein phosphatase ⁇ A ⁇ namely the A, B and C subunits.
  • the highly purified enzyme had a specific activity of 223.5 units per mg of protein.
  • protein phosphatase-2A Like other previously characterized forms of protein phosphatase-2A, protein phosphatase-2A ! from CD 4+ T cells was not inhibited by inhibitor-2 but inhibited by okadaic acid and activated by protamine. Preparation of a weak peptide compound activator of protein phosphatase-2Al. (NORAPRO-2002).
  • NORAPRO-2002 a weak peptide compound activator of protein phosphatase-2Al was prepared by chemical synthesis on an automated Solid Phase Peptide Synthesizer. Following synthesis, it was cleaved and .purified by reverse phase HPLC on a C 18 column.
  • the structure of NORAPRO-2000 is: HSRIGVTRQRRARNGASRS.
  • the molecular mass of NORAPRO-2000 was determined by MALDI ToF MS. The purified material, a white solid was readily dissolved in and reconstituted in water at - 1-2 mg/ml.
  • NORAPRO-2002 The effect of NORAPRO-2002 on the activity of protein phosphatase-2A ls the major form of protein phosphatase-2A in Jurkat cells, was determined in vitro. NORAPRO- 2002 activated protein phosphatase-2Ai by -2 fold with half maximal activation occuring at around 200 nM. The effect of NORAPRO-2000 was biphasic. (FIG. 1).
  • NORAPRO-2002 and SYRAPRO-2000 activated protein phosphatase-2Al by 2 fold with half maximal activation occuring at around 200 nM
  • SYRAPRO-2000 activated protein phosphatase-2A 1 by 7 fold with half maximal activation occuring at around 300 nM.
  • the effects of NORAPRO-2002 and SYRAPRO-2000 were biphasic. At a concentration of above 1000 nM, the activity of protein phosphatase-2Ai dropped to normal value.
  • NORAPRO-2002 is a weak activator of protein phosphatase-2Al.
  • FIG. 2 Effect of NORAPRO-2002 on the activities of protein phosphatase-2A enzymes in intact Jurkat cells.

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Abstract

La présente invention concerne la préparation d'un composé peptidique (NORAPRO-2002), son utilisation pour activer des enzymes protéines phosphatases-2A; son utilisation pour inhiber la prolifération cellulaire et l'induction de la mort de cellules cancéreuses; son utilisation dans le traitement de troubles de la prolifération cellulaire; et son utilisation dans le traitement de maladies neurodégénératives, telles que la maladie d'Alzheimer. Cette invention concerne également des peptides permettant d'induire la prolifération de cellules souches.
PCT/US2006/032723 2005-08-19 2006-08-21 Preparation d'un compose peptidique (norapro-2002) et son utilisation dans l'activation d'enzymes proteines phosphatases-2a WO2007022534A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013504518A (ja) * 2009-03-30 2013-02-07 ウニヴェルシテ ピエール エ マリー キュリー（パリ ６） アポトーシス促進性ペプチド

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011595A2 (fr) * 2002-07-26 2004-02-05 Institut Pasteur Vecteurs destines au transfert de molecules d'interet dans des cellules cibles
US20060014930A1 (en) * 2001-07-27 2006-01-19 Institut Pasteur Synthetic or natural peptides binding protein phosphatase 2A, identification method and uses

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060014930A1 (en) * 2001-07-27 2006-01-19 Institut Pasteur Synthetic or natural peptides binding protein phosphatase 2A, identification method and uses
WO2004011595A2 (fr) * 2002-07-26 2004-02-05 Institut Pasteur Vecteurs destines au transfert de molecules d'interet dans des cellules cibles

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013504518A (ja) * 2009-03-30 2013-02-07 ウニヴェルシテ ピエール エ マリー キュリー（パリ ６） アポトーシス促進性ペプチド

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