Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, and have been clinically used to treat cardiovascular disease. However, a paradoxical increase of reductase protein following statin treatment may attenuate the effect and increase the side effects. Here we present a previously unexplored strategy to alleviate statin-induced reductase accumulation by inducing its degradation. Inspired by the observations that cholesterol intermediates trigger reductase degradation, we identify a potent degrader, namely Cmpd 81, through structure-activity relationship analysis of sterol analogs. Cmpd 81 stimulates ubiquitination and degradation of reductase in an Insig-dependent manner, thus dramatically reducing protein accumulation induced by various statins. Cmpd 81 can act alone or synergistically with statin to lower cholesterol and reduce atherosclerotic plaques in mice. Collectively, our work suggests that inducing reductase degradation by Cmpd 81 or similar chemicals alone or in combination with statin therapy can be a promising strategy for treating cardiovascular disease.

中文翻译：

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发现一种有效的HMG-CoA还原酶降解剂，可消除他汀类药物诱导的还原酶蓄积并降低胆固醇。

他汀类药物是HMG-CoA还原酶（胆固醇生物合成的限速酶）的抑制剂，已在临床上用于治疗心血管疾病。但是，他汀类药物治疗后还原酶蛋白的反常增加可能会减弱这种作用并增加副作用。在这里，我们提出了一种以前尚未探索的策略，通过诱导他汀类药物的降解来减轻他汀类药物诱导的还原酶的积累。受胆固醇中间体触发还原酶降解的观察结果的启发，我们通过固醇类似物的构效关系分析确定了有效的降解剂，即Cmpd 81。Cmpd 81以Insig依赖的方式刺激泛素化和还原酶的降解，从而显着减少各种他汀类药物诱导的蛋白质积累。Cmpd 81可单独或与他汀类药物协同作用，以降低小鼠体内的胆固醇并减少动脉粥样硬化斑块。总的来说，我们的工作表明，单独或与他汀类药物联合使用Cmpd 81或类似化学物质诱导还原酶降解可能是治疗心血管疾病的一种有前途的策略。