Structure-based mechanism and inhibition of cholesteryl ester transfer protein

by Selleckchem | Apr 02 2023

Purpose of review: Cholesteryl ester transfer proteins (CETP) regulate plasma cholesterol levels by transferring cholesteryl esters (CEs) among lipoproteins. Lipoprotein cholesterol levels correlate with the risk factors for atherosclerotic cardiovascular disease (ASCVD). This article reviews recent research on CETP structure, lipid transfer mechanism, and its inhibition.

Recent findings: Genetic deficiency in CETP is associated with a low plasma level of low-density lipoprotein cholesterol (LDL-C) and a profoundly elevated plasma level of high-density lipoprotein cholesterol (HDL-C), which correlates with a lower risk of atherosclerotic cardiovascular disease (ASCVD). However, a very high concentration of HDL-C also correlates with increased ASCVD mortality. Considering that the elevated CETP activity is a major determinant of the atherogenic dyslipidemia, i.e., pro-atherogenic reductions in HDL and LDL particle size, inhibition of CETP emerged as a promising pharmacological target during the past two decades. CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, were designed and evaluated in phase III clinical trials for the treatment of ASCVD or dyslipidemia. Although these inhibitors increase in plasma HDL-C levels and/or reduce LDL-C levels, the poor efficacy against ASCVD ended interest in CETP as an anti-ASCVD target. Nevertheless, interest in CETP and the molecular mechanism by which it inhibits CE transfer among lipoproteins persisted. Insights into the structural-based CETP-lipoprotein interactions can unravel CETP inhibition machinery, which can hopefully guide the design of more effective CETP inhibitors that combat ASCVD. Individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer and which in turn, guide the rational design of new anti-ASCVD therapeutics.

Comments：

Recent research has shown that CETP plays a key role in regulating plasma cholesterol levels by transferring cholesteryl esters (CEs) among lipoproteins. Genetic deficiency in CETP has been associated with a low plasma level of low-density lipoprotein cholesterol (LDL-C) and a profoundly elevated plasma level of high-density lipoprotein cholesterol (HDL-C), which correlates with a lower risk of atherosclerotic cardiovascular disease (ASCVD). However, a very high concentration of HDL-C also correlates with increased ASCVD mortality.

Inhibition of CETP has emerged as a promising pharmacological target for the treatment of ASCVD or dyslipidemia. Several CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, have been designed and evaluated in phase III clinical trials. These inhibitors increase plasma HDL-C levels and/or reduce LDL-C levels, but have shown poor efficacy against ASCVD, which has limited interest in CETP as an anti-ASCVD target.

Despite this, interest in CETP and its mechanism of action has persisted, with researchers seeking to understand the structural-based CETP-lipoprotein interactions that guide CETP inhibition machinery. Recent insights into the individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer, which in turn can guide the rational design of more effective CETP inhibitors that combat ASCVD.

Overall, recent research on CETP has advanced our understanding of its role in regulating plasma cholesterol levels and its potential as a therapeutic target for ASCVD or dyslipidemia. Ongoing research on the structural and mechanistic basis of CETP inhibition holds promise for the development of more effective anti-ASCVD therapeutics in the future.