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Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol

Jiang, Shi-You, Li, Hui, Tang, Jing-Jie, Wang, Jie, Luo, Jie, Liu, Bing, Wang, Jin-Kai, Shi, Xiong-Jie, Cui, Hai-Wei, Tang, Jie, Yang, Fan, Qi, Wei, Qiu, Wen-Wei, Song, Bao-Liang·2018·Nature Communications
DOI 10.1038/s41467-018-07590-3PMC PMC6277434
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Abstract

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.

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Metadata

Authors
Jiang, S.-Y., Li, H., Tang, J.-J., Wang, J., Luo, J., Liu, B., Wang, J.-K., Shi, X.-J., Cui, H.-W., Tang, J., Yang, F., Qi, W., Qiu, W.-W., & Song, B.-L.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-12-03
Volume
9
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-018-07590-3
PMC
PMC6277434
Cited by
173
References
6
Language
en
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