title: Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor.
abstract: Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia-ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns.
authors: Theraptosis Research Laboratory, Theraptosis SA, Pasteur BioTop, Institut Pasteur, Paris 75015, France.
authors: D
authors: D
authors: Chauvier
authors: S
authors: S
authors: Renolleau
authors: S
authors: S
authors: Holifanjaniaina
authors: S
authors: S
authors: Ankri
authors: M
authors: M
authors: Bezault
authors: L
authors: L
authors: Schwendimann
authors: C
authors: C
authors: Rousset
authors: R
authors: R
authors: Casimir
authors: J
authors: J
authors: Hoebeke
authors: M
authors: M
authors: Smirnova
authors: G
authors: G
authors: Debret
authors: A-P
authors: AP
authors: Trichet
authors: Y
authors: Y
authors: Carlsson
authors: X
authors: X
authors: Wang
authors: E
authors: E
authors: Bernard
authors: M
authors: M
authors: Hébert
authors: J-M
authors: JM
authors: Rauzier
authors: S
authors: S
authors: Matecki
authors: A
authors: A
authors: Lacampagne
authors: P
authors: P
authors: Rustin
authors: J
authors: J
authors: Mariani
authors: H
authors: H
authors: Hagberg
authors: P
authors: P
authors: Gressens
authors: C
authors: C
authors: Charriaut-Marlangue
authors: E
authors: E
authors: Jacotot
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D018696:Neuroprotective Agents; D009842:Oligopeptides; D011804:Quinolines; C568137:quinolin-2-carbonyl-VD(OMe)VAD(OMe)-CH2-O(2,6F2)Ph; D045304:Cytochromes c; D020169:Caspases