Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol.
Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol.
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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积累并降低胆固醇
DOI：
10.1038/s41467-018-07590-3
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发表时间：
2018-12-03
影响因子：
16.6
通讯作者：
Song BL
中科院分区：
文献类型：
--
作者：
Jiang SY;Li H;Tang JJ;Wang J;Luo J;Liu B;Wang JK;Shi XJ;Cui HW;Tang J;Yang F;Qi W;Qiu WW;Song BL
他汀类药物是胆固醇生物合成限速酶HMG-CoA还原酶的抑制剂，临床上用于治疗心血管疾病。然而，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，我们提出了一个以前未探索的策略，以减轻他汀类药物诱导的还原酶积累诱导其降解。受胆固醇中间体引发还原酶降解的观察的启发，我们通过甾醇类似物的结构-活性关系分析鉴定了一种有效的降解剂，即Cmpd 81。Cmpd 81以Insig依赖性方式刺激还原酶的泛素化和降解，从而显著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，降低小鼠胆固醇，减少动脉粥样硬化斑块。总的来说，我们的工作表明，通过Cmpd 81或类似的化学物质单独或与他汀类药物治疗组合诱导还原酶降解可以是治疗心血管疾病的有希望的策略。累积的HMG-CoA还原酶（HMGCR）通过反馈回路限制他汀类药物的降胆固醇作用。在这里，作者开发了一种降解HMGCR的化合物，从而降低胆固醇水平并减少动脉粥样硬化斑块。
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. Accumulated HMG-CoA reductase (HMGCR) limits the cholesterol-lowering effect of statins via a feedback loop. Here the authors developed a compound that degrades HMGCR, thus decreasing cholesterol levels and reducing atherosclerotic plaques.
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影响因子：
5.9
作者：
Buettner, Catherine;Rippberger, Matthew J.;Smith, Julie K.;Leveille, Suzanne G.;Davis, Roger B.;Mittleman, Murray A.
通讯作者：
Mittleman, Murray A.
影响因子：
4.8
作者：
Hannah, VC;Ou, JF;Brown, MS
通讯作者：
Brown, MS
影响因子：
4.8
作者：
Hwang, Seonghwan;Hartman, Isamu Z.;DeBose-Boyd, Russell A.
通讯作者：
DeBose-Boyd, Russell A.
DOI：
10.1073/pnas.1112831108
发表时间：
2011-12-20
影响因子：
11.1
作者：
Jo, Youngah;Lee, Peter C. W.;DeBose-Boyd, Russell A.
通讯作者：
DeBose-Boyd, Russell A.
影响因子：
25.7
作者：
Dongiovanni, Paola;Petta, Salvatore;Valenti, Luca
通讯作者：
Valenti, Luca