Abstract

Based on the interaction modes of the natural 20S proteasome inhibitors TMC-95A, we have previously discovered a dipeptide 1. To explore the SAR around compound 1, we designed and synthesized a series of dipeptides (8–38) with a fragment-based strategy. Among them, nine compounds showed significant inhibitory activities against the chymotrypsin-like activity of human 20S proteasome with IC₅₀ values at the submicromolar level, which were comparable or even superior to the parent compound 1. Meanwhile, they displayed no significant inhibition against trypsin-like and caspase-like activities of 20S proteasome. The results suggested the feasibility to design dipeptides as novel and potent 20S proteasome inhibitors.

摘要

基于天然的20S蛋白酶体抑制剂TMC-95A的相互作用模式，我们先前已经发现了二肽1。为了探索化合物1周围的SAR ，我们设计和合成了一系列基于片段策略的二肽（8–38）。其中有9种化合物对人20S蛋白酶体的胰凝乳蛋白酶样活性具有显着的抑制活性，其IC ₅₀值在亚微摩尔水平，与母体化合物1相当甚至更好。。同时，它们对20S蛋白酶体的胰蛋白酶样和半胱天冬酶样活性没有显着抑制作用。结果表明设计二肽作为新型有效的20S蛋白酶体抑制剂的可行性。