Structure-based mechanism and inhibition of cholesteryl ester transfer protein

Abstract

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. Summary 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.

Dissecting the Structural Dynamics of Authentic Cholesteryl Ester Transfer Protein for the Discovery of Potential Lead Compounds: A Theoretical Study

“…When the ligand ZINC000006242926 binds to the C-terminal domain, both the N-and C-terminal domains of CETP exhibit an obvious tendency to move toward the concave surface, and the "neck" region shows a tendency to move toward the convex surface, resulting in the curvature of the CETP convex surface increasing significantly (Figure 7C). Atomistic MD simulations have confirmed that the isolated central cavities connect and form a continuous tunnel by rotation in the β-barrel direction for lipid transport [20,42]. The increased curvature of CETP may disrupt the tunnel cavity structure and hinder CE transport.…”

“…In the DCCM plot, blue indicates a significant positive correlation, red indicates obvious anti-correlation, and white regions indicate less correlation. The binding of ZINC000006242926 to the CETP Nterminus significantly weakens the negative correlation between residues Lys180-Pro246 located near the "neck" region and the Ω4, Ω5, and Ω6 regions (Figure S8A,B), probably due to the hydrophobic interactions between ZINC000006242926 and residues Leu52, Previous research has shown that the hydrophobic interactions between the CETP inhibitors torcetrapib and anacetrapib and the CETP center may alter the flexibility of CETP, the structure of the distal β-barrel domain, and the structure-function relationship between phospholipids and Helix X, resulting in the inhibitors blocking the connection between the N-terminal and C-terminal pockets and disrupting the interaction of CETP with lipoproteins to reduce the transport of CE [20,22,23,30,34]. The screened ligand ZINC000006242926 can bind to both the N-terminal and C-terminal domains, altering the curvature of CETP and the dynamic cross-correlation between important residues, in addition to having an effect on CETP flexibility as well as the structure of both ends and helix X.…”

“…Experimental studies have demonstrated that inhibition of CETP reduces cholesterol uptake by cells within atherosclerotic plaques and enhances cholesterol effluvia [18]. CETPdeficient patients also exhibit increased HDL concentrations [19], and animal studies have shown that CETP inhibition leads to higher HDL levels and reduced ASCVD [20,21]. Several inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib, and obicetrapib, have been developed, which have shown the potential to increase plasma HDL-C levels and/or decrease LDL-C levels, thereby reducing ASCVD events [20].…”

“…CETPdeficient patients also exhibit increased HDL concentrations [19], and animal studies have shown that CETP inhibition leads to higher HDL levels and reduced ASCVD [20,21]. Several inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib, and obicetrapib, have been developed, which have shown the potential to increase plasma HDL-C levels and/or decrease LDL-C levels, thereby reducing ASCVD events [20]. To better understand the inhibition mechanism, molecular dynamics simulations have been employed to study the interactions of inhibitors with CETP.…”

“…Our previous studies have indicated that the inhibitors torcetrapib, anacetrapib, and evacetrapib reduce the flexibility of N-and C-termini and Helix X, along with the stability of hydrophobic channels, and also inhibit the formation of the CETP N-terminal opening [24]. However, clinical trial evaluations have shown that some inhibitors cause unacceptable side effects such as increased systolic blood pressure, increased aldosterone and cortisol synthesis, and non-target toxic effects, while others are ineffective in treating ASCVD [20]. Therefore, the structural characteristics of CETP and lipid transfer mechanisms need to be further investigated in order to develop more effective CETP inhibitors for ASCVD treatment.…”