(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/066376 Al 24 May 20 12 (24.05.2012) W P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07K 14/47 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/IB20 10/003 158 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (22) International Filing Date: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, 18 November 20 10 (18.11.20 10) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, (26) Publication Language: English SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicants (for all designated States except US): CENTRE NATIONAL DE LA RECHERCHE SCIEN- (84) Designated States (unless otherwise indicated, for every TIFIQUE - CNRS - [FR/FR]; 3, rue Michel Ange, F- kind of regional protection available): ARIPO (BW, GH, 7501 6 Paris (FR). UNIVERSITE DE MONTPELLIER 2 GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, - SCIENCES ET TECHNIQUES [FR/FR]; Place Eugene ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Bataillon, F-34095 MONTPELLIER CEDEX (FR). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (72) Inventors; and MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (75) Inventors/Applicants (for US only): BARRERE, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Stephanie [FR/FR]; 5, rue des Mattes, F-34230 Vendemi- ML, MR, NE, SN, TD, TG). an (FR). NARGEOT, Joel [FR/FR]; 9, rue de Nazareth, Bat. Gl, F-34090 Montpellier (FR). LEBLEU, Bernard Declarations under Rule 4.17 : [FR/FR]; 140, rue Pioch de Boutonnet, Bat. Al, F-34090 — of inventorship (Rule 4.17(iv)) Montpellier (FR). BOISGUERIN, Prisca [FR/FR]; 8, rue Published: la Preneuse, F-30240 Le Grau-du-Roi (FR). PIOT, Chris- tophe [FR/FR]; 172 avenue de Peyre Grosse, F-34980 — with international search report (Art. 21(3)) Saint Clement de Riviere (FR). — with sequence listing part of description (Rule 5.2(a)) (74) Agents: POPPING, Barbara et al; Cabinet Plasseraud, 52, rue de la Victoire, F-75440 Paris Cedex 09 (FR). © © (54) Title: INHIBITORS OF APOPTOSIS AND USES THEREOF (57) Abstract: The invention relates to fragments of the Daxx and FADD proteins inhibiting cell apoptosis mediated by the Fas re - ceptor. The invention also relates to conjugates comprising said fragments, and to the medical applications of said fragments and conjugates. INHIBITORS OF APOPTOSIS AND USES THEREOF FIELD OF THE INVENTION The invention relates to inhibitors of apoptosis and to their uses, in particular medical treatments. INTRODUCTION Coronary heart disease is the leading cause of death worldwide, and 3.8 million men and 3.4 million women die of the disease each year. As the population grows older and comorbidities (e.g., obesity and metabolic syndrome) become more prevalent, as in recent years, the enormous public health burden caused by ischemic heart disease is likely to increase even further (reviewed in Yellon et al, N Engl J Med 2007; 357: 1121-1 135). Myocardial infarction is the leading cause of death in both Europe and the United states. Myocardial infarction (MI) or acute myocardial infarction (AMI) - commonly known as a heart attack - is the interruption of blood supply to part of the heart, causing cell death. This is most commonly due to occlusion (blockage) of a coronary artery. AMI remains a frequent (more than 1.5 million new cases per year in the United States) and disabling (leading to heart failure) disease. Infarct size is a major determinant of myocardial functional recovery and mortality after AMI. Currently, the most effective way to limit infarct size is to reperfuse the jeopardized myocardium as soon as possible with the use of coronary angioplasty or thrombolysis and to prevent reocclusion of the coronary artery with the use of antiplatelet therapy. Reperfusion, or restoration of blood flow to the ischemic myocardium, is achieved with thrombolytic therapy that dissolves the thrombus or through dilatation of the occluded artery by percutaneous coronary angioplasty. Reperfusion is necessary for the salvage of myocardial cells and cardiac function in general; however, reperfusion initiates a cascade of events that leads to 'reperfusion injury' (RI). This also occurs following recovery from cardioplegic arrest of the heart during bypass surgery. RI is characterized by arrhythmias, endothelial dysfunction leading to the no-reflow phenomenon, myocardial stunning (reversible loss of myocardial contractility) and, ultimately, cell death. Lethal reperfusion injury culminates in apoptotic death of cardiac cells that were viable immediately before myocardial reperfusion. The participation of a highly- regulated form of cell death during myocardial ischemia/reperfusion may lead to novel therapeutic interventions in the reperfusion phase. However, the apoptosis signalling pathways functional during myocardial ischemia/reperfusion have not yet been fully delineated in vivo. Finding new treatments for inhibiting apoptosis, and in particular for treating myocardial infarction and reperfusion injury, thus constitute a real challenge to protect cardiac function and to save lives. SUMMARY OF THE INVENTION The invention is based on the finding that it is possible to decrease apoptosis of cardiac cells after myocardial infarction by inhibiting the Fas signalling pathway. The Fas Receptor upon binding to the FasL (Fas Ligand) trimerizes and induces apoptosis through a cytoplasmic domain called DD (Death Domain) that interacts with signalling adaptors like FAF-1 (Fas-Associated Factor- 1), FADD (Fas- Associated Death Domain), Daxx (Death-Domain Associated protein), FAP-1, FLASH (FLICE-associated huge) and RIP (Receptor-Interacting Protein). Daxx and FADD bind independently to Fas and activate distinct apoptotic pathways. Daxx can enhance Fas-mediated apoptosis by activating the INK kinase cascade, culminating in the phosphorylation and activation of transcription factors such as c- Jun. In contrast, FADD triggers, through a cascade of caspases signalling, the release of mitochondrial pro-apoptotic factors like CytoC (Cytochrome-C) and SMAC (Second Mitochondria-derived Activator of Caspases) also called Diablo. The inventors have shown that the inhibition of the interaction of Fas Receptor with Daxx and FADD leads to a strong decrease of the apoptosis of cardiac cells after myocardial infarction. The invention thus relates to peptides consisting of : - a fragment of at most 130 amino acids of an amino acid sequence having at least 80% identity with SEQ ID NO:l, wherein said fragment comprises the amino acid sequence as shown in SEQ ID NO:6, or - a fragment at most 130 amino acids of an amino acid sequence having at least 80% identity with SEQ ID NO:8, wherein said fragment comprises the amino acid sequence as shown in SEQ ID NO: 12, or derivatives thereof, wherein said peptides or derivatives thereof are capable of inhibiting cell apoptosis. The invention also relates to conjugates comprising a peptide or a derivative thereof according to the invention linked to a Cell Penetrating Peptide. The invention also relates to the peptides or derivatives thereof according to the invention, or to the conjugates according to the invention, for use in a method for treatment of the human or animal body. The invention still relates to the peptides or derivatives thereof according to the invention, or to the conjugates according to the invention, for use in a method for inhibiting cell apoptosis in the human or animal body. The invention also relates to the peptides or derivatives thereof according to the invention, or to the conjugates according to the invention, for use in a method for treatment of acute myocardial infarction (AMI), cerebral infarction, organ transplantations, cardiac interventions (extra-corporally circulation and temporary vessel occlusion), or acute circulation perturbations (state of shock), in the human or animal body. The invention further relates to the peptides or derivatives thereof according to the invention, or to the conjugates according to the invention, for use in a method for treatment of ischemia, in particular cardiac ischemia, ischemic colitis, mesenteric ischemia, brain ischemia, limb ischemia or skin ischemia, in the human or animal body. The invention also relates to the peptides or derivatives thereof according to the invention, or to the conjugates according to the invention, for use in a method for treatment of reperfusion injury in the human or animal body. DEFINITIONS As used herein, the percentage of sequence identity refers to comparisons among amino acid sequences, and is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the amino acid 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 may be calculated by determining the number of positions at which the identical 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.