Screening for inhibitors of Cholesteryl Ester Transfer Protein

Cholesteryl ester transfer protein (CETP) promotes exchange and transfer of neutral lipids such ascholesteryl ester （CE）和TG between plasma lipoproteins. Evidence has been accumulating of theimportance of CETP in atherosclerosis. Thereforeinhibition of CETP是proposed as a novel target for anti-atherosclerotic drugs. Interestingly，the mechanism of CETP-mediated lipid transfer is still unclear. In fact，small molecules modulating the CETP activity been searched for extensively for therapeutic andbiochemical purposes.Over twenty thousand samples of microbial culture broths subjected to ourscreening program for CETP inhibitors. Finally，我们发现的错误从一个fungal strain，and ferroverdins from an actinomycete strain，正如novel CETP inhibitors.我们也观察已知的功能metabolites，sclerotiorin originally isolated as a yellow pigment and L681512 compounds isolated as elastaseinhibitors, inhibit CETP activity.From the model reaction，sclerotiorin can react with a primary amine such as N-terminal cysteine and/or lysines in CETPmolecule to form a covalent bond Among CETP inhibitors of natural origin ferroverdin B show verypotent CETP inhibition with a nanomolar IC - D250 - D2 value. Ex体内efficacy was shown usingtransgenic mice for sclerotiorin and L681512。

Cholesteryl ester transfer protein (CETP) promotes exchange and transfer of neutral lipids such as cholesteryl ester (CE) and TG between plasma lipoproteins. Evidence has been accumulating of the importance of CETP in atherosclerosis. Therefore, inhibition of CETP is proposed as a novel target for anti-atherosclerotic drugs. Interestingly, the mechanism of CETP-mediated lipid transfer is still unclear. In fact, small molecules modulating the CETP activity have been searched for extensively for therapeutic and biochemical purposes.Over twenty thousand samples of microbial culture broths were subjected to our screening program for CETP inhibitors. Finally, we discovered erabulenols from a fungal strain, and ferroverdins from an actinomycete strain, as novel CETP inhibitors. We also observed that known fungal metabolites, sclerotiorin originally isolated as a yellow pigment and L681512 compounds isolated as elastase inhibitors, inhibit CETP activity.From the model reaction, sclerotiorin can react with a primary amine such as N-terminal cysteine and/or lysines in CETP molecule to form a covalent bond. Among CETP inhibitors of natural origin ferroverdin B show very potent CETP inhibition with a nanomolar ICィイD250ィエD2 value. Ex vivo efficacy was shown using transgenic mice for sclerotiorin and L681512.