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A Novel CETP Inhibitor for Cholesterol Control IB-3143

Berkeley Lab researchers Gang Ren and Lei Zhang have developed new inhibitors of cholesteryl ester transfer protein (CETP), which has been the focus of research into drugs that regulate levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL), also known respectively as “good” and “bad” cholesterol. CETP is thought to play a critical role in raising good cholesterol and reducing bad cholesterol levels by transferring the fatty substances from HDL to LDL. Using a transmission electron microscopy (TEM) protocol called optimized negative-staining (OpNS) and cryo-positive-staining (Cryo-PS), Ren and his team observed images of HDL and LDL molecules connected as if by a bridge of the two ends of banana-shaped CETP. These images supported a model in which CETP serves as a tunnel that pipes cholesteryl esters from HDL to LDL. Based on that imagery, the Berkeley Lab researchers screened for antibodies that could bind to and block either end of the banana-shaped CETP. Laboratory tests showed that when the antibody H300 blocked one end, the C-terminal (Figure 1), HDL molecules retained their diameter during incubation with LDL and CETP. In the absence of that antibody, the HDL molecules decreased in size, suggesting that the cholesteryl esters within them had been transferred to LDL. In addition, Antibody-N, which was custom-designed to bind to CETP at its other end —the N-terminal —, also prevented HDL-cholesterol transport to the LDL molecule. Cholesterol-regulating drugs are potent weapons in the effort to prevent heart disease. Statins that reduce levels of LDL are among the most successful pharmaceuticals ever made; but efforts to develop drugs that increase levels of HDL have failed. Those drugs were based on a different and previously accepted model that presumed that CETP shuttled these esters from HDL to LDL, like a freighter collecting and delivering its cargo — and did so docked parallel to the much larger lipoproteins, rather than pushing into them from both ends as revealed by the TEM imagery observed in the Berkeley Lab research. The Berkeley Lab research indicates that either H300 or Antibody-N, as well as small molecules of similar surface morphology, will block the cholesteryl ester transfer mechanism, and that blocking either end of CETP could serve as the basis for effective drugs that will raise levels of good cholesterol.
A new and refined target for CETP inhibition - Highly specific receptor site - Pathway for small-molecule therapeutics
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Patent Status: 
Published patent application WO/2013/075040 available at www.wipo.int. Available for licensing or collaborative research.
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