Nature Communications publishes new findings by Song Baoliang’s team——discovering a potent HMG-CoA reductase degrader
Time:Dec 24, 2018  Clicks:

On December 3rd, 2018, Prof. Song Baoliang’s team from College of Life Sciences, Wuhan University published online their newest research results in Nature Communications (Impact Factor/IF=12.353). They discovered the potent HMG-CoA reductase (HMGCR) degrader Cmpd 81 that eliminates statin-induced reductase accumulation and lowers cholesterol.

Postdoctoral researchers Jiang Shiyou and Tang Jingjie in Prof. Song’s team and Dr. Li Hui from East China Normal University (ECNU) are co-first authors. Associate Professor Qiu Wenwei from ECNU and Prof. Song are co-corresponding authors. Co-authors include Prof. Tang Jie and Prof. Yang Fan from ECNU, Qi Wei, a researcher from ShanghaiTech University, Associate Professor Luo Jie and Associate Professor Shi Xiongjie from WHU, etc. This research is funded by the National Natural Science Foundation (NNSF) of China, Ministry of Science and Technology (MOST) of China, 111 Project of Ministry of Education of China, Shanghai Science and Technology Council  and The National Key Technology R&D Program.

Long-term elevated serum level of cholesterol, recognized as one of the major risk factors for cardiovascular disease (CVD), can lead to atherosclerosis, a cause of cardiovascular disease (CVD). Statins are inhibitors of HMGCR, the rate-limiting enzyme of cholesterol biosynthesis, and have been clinically used to treat CVD. However, the paradoxical increase of reductase protein following statin treatment may attenuate the curative effect and increase the side effects.

Based on the previous findings on HMGCR degradation mechanism, Prof. Song’s team in collaboration with Associate Professor Qiu’s team, have discovered Cmpd 81, an super compound and promoter of HMGCR degradation through a series of compound designing, optimizing and analysis. This research indicates that Cmpd 81 can prevent statin-induced accumulation of HMGCR, reduce serum cholesterol level and decrease atherosclerosis. Further structure–activity relationship studies reveal that Cmpd 81 stimulates ubiquitination and degradation of reductase in an Insig-dependent manner, thus dramatically reducing protein accumulation induced by various statins, as shown in the figure below. Cmpd 81 can act alone to lower cholesterol and reduce atherosclerotic plaques in mice and more effectively synergistically with statin. Collectively, their work suggests that inducing HMGCR degradation by Cmpd 81 or similar chemicals alone and especially in combination with statin therapy can be a promising strategy for lowering cholesterol and treating cardiovascular disease. Besides, the results suggest that the HMGCR (TM1-8)-GFP reporting system can be used as a reliable assay to screen for compounds promoting HMGCR degradation. Both the reporting system and this class of compounds (take Cmpd 81 as a representative) have been applied for a patent.

A working model of Cmpd 81 in lowering cholesterol synthesis. All clinically used statins dramatically induce compensatory increase of HMGCR, and the increased HMGCR proteins would blunt statins’ efficacy. However, Cmpd 81 remarkably degrades statins-induced HMGCR protein through the ubiquitin-proteasome pathway to lower the cholesterol synthesis, and to improve the efficacy of statins.

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

(Rewritten by Lu Xinqiang, edited by Zheng Lingling, Shen Yuxi, Hu Sijia )