Abstract
Cholesteryl ester transfer protein (CETP) has been identified as a novel target for increasing HDL cholesterol levels. In this report, we describe the biochemical characterization of anacetrapib, a potent inhibitor of CETP. To better understand the mechanism by which anacetrapib inhibits CETP activity, its biochemical properties were compared with CETP inhibitors from distinct structural classes, including torcetrapib and dalcetrapib. Anacetrapib and torcetrapib inhibited CETP-mediated cholesteryl ester and triglyceride transfer with similar potencies, whereas dalcetrapib was a significantly less potent inhibitor. Inhibition of CETP by both anacetrapib and torcetrapib was not time dependent, whereas the potency of dalcetrapib significantly increased with extended preincubation. Anacetrapib, torcetrapib, and dalcetrapib compete with one another for binding CETP; however anacetrapib binds reversibly and dalcetrapib covalently to CETP. In addition, dalcetrapib was found to covalently label both human and mouse plasma proteins. Each CETP inhibitor induced tight binding of CETP to HDL, indicating that these inhibitors promote the formation of a complex between CETP and HDL, resulting in inhibition of CETP activity.
Highlights
Cholesteryl ester transfer protein (CETP) has been identified as a novel target for increasing HDL cholesterol levels
Anacetrapib is a potent inhibitor of CETP neutral lipid transfer activity Anacetrapib has been shown to inhibit CETP activity, thereby significantly raising HDL cholesterol (HDL-C) levels in humans [59, 61, 67]
A description of anacetrapib’s biochemical characterization and mechanism of CETP inhibition has not been reported. To better understand both the similarities and differences between anacetrapib and two additional CETP inhibitors, torcetrapib and dalcetrapib, we characterized each inhibitor in a series of biochemical assays
Summary
Cholesteryl ester transfer protein (CETP) has been identified as a novel target for increasing HDL cholesterol levels. Anacetrapib and torcetrapib inhibited CETP-mediated cholesteryl ester and triglyceride transfer with similar potencies, whereas dalcetrapib was a significantly less potent inhibitor. Cholesteryl ester transfer protein (CETP), a hydrophobic plasma glycoprotein, is a promising target for raising circulating HDL-C concentrations in humans. CETP is secreted primarily from the liver and plays a critical role in HDL metabolism by facilitating the exchange of cholesteryl esters (CE) from HDL for triglycerides (TG) in apoBcontaining lipoproteins, such as LDL and VLDL [24, 25] This activity both directly lowers the cholesterol levels of HDL-C and enhances HDL catabolism by providing HDL with the TG substrate of hepatic lipase [26, 27]. To firmly establish a causal link between CETP and CHD risk, either additional genetic analyses with larger populations of individuals or pharmacological inhibition of CETP will be required
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