Rational Design of Calpain Inhibitors Based on Calpastatin Peptidomimetics

详细信息    查看全文

• 作者：Kristin E. Low ; Spencer Ler ; Kevin J. Chen ; Robert L. Campbell ; Jennifer L. Hickey ; Joanne Tan ; Conor C. G. Scully ; Peter L. Davies ; Andrei K. Yudin ; Serge Zaretsky
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：59
• 期：11
• 页码：5403-5415
• 全文大小：695K
• 年卷期：0
• ISSN：1520-4804

文摘

Our previously reported structures of calpain bound to its endogenous inhibitor calpastatin have motivated the use of aziridine aldehyde-mediated peptide macrocyclization toward the design of cyclic peptides and peptidomimetics as calpain inhibitors. Inspired by nature’s hint that a β-turn loop within calpastatin forms a broad interaction around calpain’s active site cysteine, we have constructed and tested a library of 45 peptidic compounds based on this loop sequence. Four molecules have shown reproducibly low micromolar inhibition of calpain-2. Further systematic sequence changes led to the development of probes that displayed increased potency and specificity of inhibition against calpain over other cysteine proteases. Calculated K_i values were in the low micromolar range, rivaling other peptidomimetic calpain inhibitors and presenting an improved selectivity profile against other therapeutically relevant proteases. Competitive and mixed inhibition against calpain-2 was observed, and an allosteric inhibition site on the enzyme was identified for a noncompetitive inhibitor.