Meara J P, Rich D H
School of Pharmacy, University of Wisconsin, Madison 53705, USA.
J Med Chem. 1996 Aug 16;39(17):3357-66. doi: 10.1021/jm950445b.
Analogs of the epoxysuccinyl peptide cysteine proteinase inhibitor, EP-475 (2a), in which the free carboxylate has been replaced by hydroxamic acid, amide, methyl ketone, hydroxyl, and ethyl ester functionalities, have been synthesized. Individual rate constants of inhibition of papain were determined for these inhibitors. The results show that a carbonyl-containing functionality is necessary for good activity. The pH dependence of the inhibition of papain was determined for a nonionizable EP-475 (2a) analog; inhibition was found to depend on two acidic ionizations (pKas of 3.93 and 4.09) of papain. Implications for the mechanism of action of epoxysuccinyl peptides with papain are discussed.
已合成环氧琥珀酰肽半胱氨酸蛋白酶抑制剂EP - 475（2a）的类似物，其中游离羧酸盐已被异羟肟酸、酰胺、甲基酮、羟基和乙酯官能团取代。测定了这些抑制剂对木瓜蛋白酶的个体抑制速率常数。结果表明，含羰基的官能团对于良好的活性是必需的。测定了一种非离子化的EP - 475（2a）类似物对木瓜蛋白酶抑制作用的pH依赖性；发现抑制作用取决于木瓜蛋白酶的两个酸性电离（pKa分别为3.93和4.09）。讨论了环氧琥珀酰肽与木瓜蛋白酶作用机制的相关问题。
