1999 Fiscal Year Final Research Report Summary
Screening for inhibitors of Cholesteryl Ester Transfer Protein
| Project/Area Number |
09480147
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bioorganic chemistry
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| Research Institution | The Kitasato Institute |
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Principal Investigator |
TOMODA Hiroshi Research Center for Biological Function, The Kitasato Institute, Director, 生物機能研究所, 副所長 (70164043)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Yoko Research Center for Biological Function, The Kitasato Institute, Chief Researcher, 生物機能研究所, 室長 (80197186)
TABATA Noriko Research Center for Biological Function, The Kitasato Institute, Researcher, 生物機能研究所, 研究員 (60260080)
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| Project Period (FY) |
1997 – 1999
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| Keywords | CETP / inhibitor / microbial origin / cholesteryl ester / Ferroverdin / Erabulenol |
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| Research Abstract |
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.
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Research Products
(12 results)
