Peptides Useful As Dual Caspase-2/-6 Inhibitors And Their Biological Applications

Abstract

The invention relates to peptides having a core sequence selected in the group comprising: SEQ ID No.1: VDEAD, SEQ ID No.2: LDEGD, SEQ ID No.3: VDEGD, SEQ ID No.4: VDESD, SEQ ID No.5: LDEKD, SEQ ID No.6: FDESD, SEQ ID No.7: LDEAD, application as inhibitors of caspase-2 and/or -6 activity.

1 . Peptides having a core sequence selected in the group comprising:
 SEQ ID No.1: VDEAD   SEQ ID No.2: LDEGD   SEQ ID No.3: VDEGD   SEQ ID No.4: VDESD   SEQ ID No.5: LDEKD   SEQ ID No.6: FDESD   SEQ ID No.7: LDEAD   
     
     
         2 . Peptides according to  claim 1  having a N-terminal protecting group and/or a C-terminal protecting group. 
     
     
         3 . Peptides according  claim 2 , wherein the N-terminal protecting group is M=A-(CH 2 ) n1 , wherein
 n1=0 to 20,   M is H when n1=0,   A is a C1-C20 alkyl, one or several condensed cycles and/or heterocycles,   A, when different from H, and when n1 is above 2, being saturated or unsaturated and optionally substituted by one or several groups such as H, OH, OR a , (CH 2 ) n1 OH, (CH 2 ) n1 OR a , COOH, COOR a , (CH 2 ) n COOH, (CH 2 ) n1 COOR a , C 1 -C 3  alkyl or cycloalkyl, (CH 2 ) n1 -alkyl, CO—NH-alkyl, Ar, (CH 2 ) n1 —Ar, CO—NH—Ar, halogen, CF 3 , SO 3 H, (CH 2 ) x  PO 3 H 2 , B(OH) 2 , NO 2 , SO 2 NH 2 , SO 2 NHR a ; with x=0, 1 or 2; R a  being a C 1 -C 3  alkyl and Ar being an optionally substituted aryl or heteroaryl group,   or
 A is one or several aminoacid residues 
   or
 A represents a chromophore, a fluorescent, luminescent, absorbing (UV to near IR) group, a radioisotope, metallic particles such as used in electronic microscopy, a colorimetric group, biotin/streptavidin/neutravidin labeling systems, or analogues. 
   
     
     
         4 . Peptides according to  claim 2 , wherein the peptides have a C-terminal protecting group X, with X being H or a carboxy protecting group selected in the group comprising OR b , NHR b , SR b , CH 2 OR b , CH 2 NHR b , CH 2 SR b , CH 2 OR b  and CH 2 Y, in which R b =acyl, alkyl, substituted alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, optionally condensed with one or several cycles and/or heterocycles, a C1-C20 substituted or unsubstituted aliphatic, aralkyl carbocyclic alkyl carbocyclic, or heterocyclic group, optionally condesed with one or several aromatic or not cycles and Y is an halogen atom (F, Cl, Br or I) or NO 2 , or X represents a chromophore, a fluorescent, luminescent, absorbing (UV to near IR) group, a radioisotope, metallic particles such as used in electronic microscopy, a colorimetric group, biotin/streptavidin/neutravidin labeling systems, or analogues. 
     
     
         5 . Pharmaceutical compositions comprising a therapeutically effective amount of at least one peptide or inhibitor according to  claim 1  in association with a pharmaceutically acceptable carrier. 
     
     
         6 . The pharmaceutical compositions according to  claim 5  for administration by oral, nasal, local (subcutaneous, intracerebroventricular, intracerebral implantation of material impregnated with compounds or pharmaceutical compositions, intracerebral implantation of instrumentation for mechanical delivery, for example) or systemic (for example: intraperitoneal, intravenous . . . ) administration to reduce cell death. 
     
     
         7 . The pharmaceutical compositions according to  claim 5  for the treatment of pathological situation including hypoxia-ischemia (H-I) H-I (ischemia with or without hypoxia/hypoglycaemia) injuries and stroke-like situations (cerebral, renal, cardiac failure, for example). 
     
     
         8 . The pharmaceutical compositions according to  claim 5 , for the treatment of pathological situation including cerebral hypoxia-ischemia (H-I) (ischemia with or without hypoxia/hypoglycaemia) injuries and stroke-like situations (cerebral, renal, cardiac failure, for example). 
     
     
         9 . The pharmaceutical compositions according to  claim 5 , for the treatment of neuronal death particularly in global or focal H-I (ischemia with or without hypoxia/hypoglycaemia) injuries and stroke-like situations (cerebral, renal, cardiac failure, for example). 
     
     
         10 . The pharmaceutical compositions according to  claim 5 , for the treatment of neuronal death particularly in adult, fetal or perinatal H-I (ischemia with or without hypoxia/hypoglycaemia) injuries and stroke-like situations (cerebral, renal, cardiac failure, for example). 
     
     
         11 . The pharmaceutical compositions according to  claim 5 , for the treatment of neuronal death particularly in transient or permanent H-I (ischemia with or without hypoxia/hypoglycaemia) injuries and stroke-like situations (cerebral, renal, cardiac failure, for example). 
     
     
         12 . The pharmaceutical compositions according to  claim 5 , for the treatment of neuronal death particularly H-I (ischemia with or without hypoxia/hypoglycaemia) injuries and stroke-like situations brain injuries with or without reperfusion situation (cerebral, renal, cardiac failure, for example). 
     
     
         13 . The pharmaceutical compositions according to  claim 5 , or the treatment of neuronal death particularly in Middle Cerebral Artery Occlusion (MCAO) in adult, fetal or perinatal H-I. 
     
     
         14 . The pharmaceutical compositions according to  claim 5 , for the treatment of neuronal death particularly when at least one or more of the following pathological events are combined: global or focal, transient or permanent, adult or fetal or perinatal H-I (ischemia with or without hypoxia/hypoglycaemia) at cerebral level, or at the level of whole body) with or without reperfusion. 
     
     
         15 . The pharmaceutical compositions according to  claim 5 , for the treatment of neuronal death particularly when at least one or more of the following brain injury. 
     
     
         16 . The pharmaceutical compositions according to  claim 5 , for the treatment of neuronal death particularly when at least one or more of the following perinatal brain injury. 
     
     
         17 . The pharmaceutical compositions according to  claim 5 :
 to prevent and/or treat cell death during chronic degenerative diseases e.g. neurodegenerative disease including Alzheimer's disease, Huntingtons' disease, Parkinsons' disease, Multiple sclerosis, amyotrophic lateral sclerosis, spinobulbar atrophy, prion disease, dementia or   to prevent and/or to treat epilepsy or epilepstogenesis or   to prevent and/or treat apoptosis during spinal cord injury, or to prevent and/or treat apoptosis resulting from traumatic brain injury, or   to provide neuroprotective effect, or   to provide cerebroprotective effect, or   to prevent and/or treat cytotoxic T cell and natural killer cell-mediated apoptosis associated with autoimmune disease and transplant rejection, or   to prevent cell death of cardiac cells including heart failure, cardiomyopathy, viral infection or bacterial infection of heart, myocardial ischemia, myocardial infarct, and myocardial ischemia, coronary artery by-pass graft, or   to prevent and/or treat mitochondrial drug toxicity e.g. as a result of chemotherapy or HIV therapy, or   to prevent cell death during viral infection or bacterial infection, or   to prevent and/or treat inflammation or inflammatory diseases, inflammatory bowel disease, sepsis and septic shock, or   to prevent cell death from follicule to ovocyte stages, from ovocyte to mature egg stages (Nutt et al. 2005; Bergeron et al., 1998); and sperm (for example, methods of freezing and transplanting ovarian tissue, artificial fecondation), or   to preserve fertility in women and men after chemotherapy, or   to preserve fertility in females and males animals, or   to prevent and/or treat, macular degenerescence and glaucoma, or to prevent and/or treat acute hepatitis, chronic active hepatitis, hepatitis-B, and hepatitis-C,   to prevent hair loss, and said hair loss due-to male-pattern baldness, radiation, chemotherapy or emotional stress, or   to treat or ameliorate skin damage (due to exposure to high level of radiation, heat, burns, chemicals, sun, and autoimmune diseases), or   to prevent cell death of bone marrow cells in myelodysplastic symdromes, or   to treat pancreatisis, or   to treat respiratory syndrome, or   to treat and/or prevent death of gastrointestinal lining epithelial cells, or   to treat osteoarthitis, rheumatoid arthritis, psoriasis, glomerulonephritis, atheroscerosis, and graft versus host disease, or   to treat retinal pericyte apoptosis, retinal neurons apoptosis, glaucoma, retinal damages, macular degeneration resulting from ischemia, diabetic retinopaty, or other trauma, or   to treat disease states associated with an increase of apoptosis, or   to prevent cell death in vegetals (for example: plants, flowers, thallophytes (mushrooms, seaweed) . . . )   
     
     
         18 . An in vitro method of inhibition of caspase-2 and/or 6 activity comprising using a peptide according to  claim 1 .