Design, Synthesis, and Optimization of Novel Epoxide Incorporating Peptidomimetics as Selective Calpain Inhibitors

详细信息    查看全文

• 作者：Isaac T. Schiefer ; Subhasish Tapadar ; Vladislav Litosh ; Marton Siklos ; Rob Scism ; Gihani T. Wijewickrama ; Esala P. Chandrasena ; Vaishali Sinha ; Ehsan Tavassoli ; Michael Brunsteiner ; Mauro Fa鈥? Ottavio Arancio ; Pavel Petukhov ; Gregory R. J. Thatcher
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 8, 2013
• 年：2013
• 卷：56
• 期：15
• 页码：6054-6068
• 全文大小：663K
• 年卷期：v.56,no.15(August 8, 2013)
• ISSN：1520-4804

文摘

Hyperactivation of the calcium-dependent cysteine protease calpain 1 (Cal1) is implicated as a primary or secondary pathological event in a wide range of illnesses and in neurodegenerative states, including Alzheimer鈥檚 disease (AD). E-64 is an epoxide-containing natural product identified as a potent nonselective, calpain inhibitor, with demonstrated efficacy in animal models of AD. By use of E-64 as a lead, three successive generations of calpain inhibitors were developed using computationally assisted design to increase selectivity for Cal1. First generation analogues were potent inhibitors, effecting covalent modification of recombinant Cal1 catalytic domain (Cal1_cat), demonstrated using LC鈥揗S/MS. Refinement yielded second generation inhibitors with improved selectivity. Further library expansion and ligand refinement gave three Cal1 inhibitors, one of which was designed as an activity-based protein profiling probe. These were determined to be irreversible and selective inhibitors by kinetics studies comparing full length Cal1 with the general cysteine protease papain.