Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality

作     者：Lee, D Long, SA Adams, JL Chan, G Vaidya, KS Francis, TA Kikly, K Winkler, JD Sung, CM Debouck, C Richardson, S Levy, MA DeWolf, WE Keller, PM Tomaszek, T Head, MS Ryan, MD Haltiwanger, RC Liang, PH Janson, CA McDevitt, PJ Johanson, K Concha, NO Chan, W Abdel-Meguid, SS Badger, AM Lark, MW Nadeau, DP Suva, LJ Gowen, M Nuttall, ME 

作者机构：SmithKline Beecham Pharmaceut Dept Med Chem King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Biomol Discovery King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Immunol King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Immunopharmacol King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Mol Biol King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Mol Recognit King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Phys & Struct Chem King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Prot Biochem King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Biol Struct King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Bone & Cartilage Biol King Of Prussia PA 19406 USA 

出 版 物：《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)

年 卷 期：2000年第275卷第21期

页      面：16007-16014页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

主　　题：氨基酸氯甲基酮类/药理学 细胞凋亡 结合部位 喜树碱/药理学 半胱氨酸天冬氨酸蛋白酶3 半胱氨酸天冬氨酸蛋白酶7 软骨细胞/药物作用 胶原/遗传学 结晶学 X线 酶抑制剂/化学 酶抑制剂/药理学 靛红/类似物和衍生物 模型 分子 分子结构 中性白细胞/药物作用 中性白细胞/酶学 骨关节炎/药物疗法 启动区 遗传 重组蛋白质类/化学 磺胺类/化学 磺胺类/药理学 动物 人类 小鼠 

摘      要：Caspases have been strongly implicated to play an essential role in apoptosis, A critical question regarding the role(s) of these proteases is whether selective inhibition of an effector caspase(s) will prevent cell death. We have identified potent and selective non-peptide inhibitors of the effector caspases 3 and 7, The inhibition of apoptosis and maintenance of cell functionality with a caspase 3/7-selective inhibitor is demonstrated for the first time, and suggests that targeting these two caspases alone is sufficient for blocking apoptosis, Furthermore, an x-ray co-crystal structure of the complex between recombinant human caspase 3 and an isatin sulfonamide inhibitor has been solved to 2.8-Angstrom resolution, In contrast to previously reported peptide-based caspase inhibitors, the isatin sulfonamides derive their selectivity for caspases 3 and 7 by interacting primarily with the S-2, subsite, and do not bind in the caspase primary aspartic acid binding pocket (S-1), These inhibitors blocked apoptosis in murine bone marrow neutrophils and human chondrocytes, Furthermore, in camptothecin-induced chondrocyte apoptosis, cell functionality as measured by type II collagen promoter activity is maintained, an activity considered essential for cartilage homeostasis. These data suggest that inhibiting chondrocyte cell death with a caspase 3/7-selective inhibitor may provide a novel therapeutic approach for the prevention and treatment of osteoarthritis, or other disease states characterized by excessive apoptosis.