Theraptosis Research Laboratory, Theraptosis SA, Pasteur BioTop, Institut Pasteur, Paris 75015, France.
Cell Death Dis. 2011 Sep 1;2(9):e203. doi: 10.1038/cddis.2011.87.
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.
新生儿的脑保护仍然是一个具有挑战性的优先事项，代表着完全未满足的医疗需求。细胞凋亡蛋白酶的药理学抑制似乎是一种有前途的神经保护策略。从转化医学的角度来看，我们开发了一种基于五肽的 II 组细胞凋亡蛋白酶抑制剂，TRP601/ORPHA133563，它可以到达大脑，并抑制细胞凋亡蛋白酶的激活、细胞色素 c 的线粒体释放和体内细胞凋亡。单次给予 TRP601 可在 6 小时的治疗时间窗内保护新生啮齿动物大脑免受兴奋性毒性、缺氧缺血和围产期动脉卒中的影响，并且对生理参数没有不良影响。在啮齿动物和犬类新生儿中的安全药理学研究和毒理学研究表明，TRP601 是进一步开发药物以治疗人类新生儿缺血性脑损伤的先导化合物。
