Journal
NATURE
Volume 406, Issue 6792, Pages 203-207Publisher
MACMILLAN PUBLISHERS LTD
DOI: 10.1038/35018119
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Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for triglyceride in very low density lipoprotein (VLDL)(1,2). This process decreases the level of antiatherogenic HDL cholesterol and increases pro-atherogenic VLDL and low density lipoprotein (LDL) cholesterol, so CETP is potentially atherogenic(3-9). On the other hand, CETP could also be anti-atherogenic(10-14), because it participates in reverse cholesterol transport (transfer of cholesterol from peripheral cells through the plasma to the liver)(15). Because the role of CETP in atherosclerosis remains unclear, we have attempted to develop a potent and specific CETP inhibitor. Here we describe CETP inhibitors that form a disulphide bond with CETP, and present one such inhibitor (JTT-705) that increases HDL cholesterol, decreases non-HDL cholesterol and inhibits the progression of atherosclerosis in rabbits. Our findings indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential antiatherogenic drug.
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