Screening for inhibitors of Cholesteryl Ester Transfer Protein

胆固醇酯转移蛋白抑制剂的筛选

• 批准号: 09480147
• 负责人: TOMODA Hiroshi
• 金额: $ 2.88万
• 依托单位: The Kitasato Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09480147/
• 关键词: CETP; inhibitor; microbial origin; cholesteryl ester; Ferroverdin; Erabulenol; Pyripyropene誘導体; 放射菌代謝産物; エラブレノール; 糸状菌代謝産物

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.

胆固醇酯转运蛋白（CETP）促进中性脂质如胆固醇酯（CE）和甘油三酯（TG）在血浆脂蛋白之间的交换和转移。越来越多的证据表明CETP在动脉粥样硬化中的重要性。因此，抑制CETP被认为是抗动脉粥样硬化药物的新靶点。有趣的是，CETP介导的脂质转移的机制仍然不清楚。事实上，调节CETP活性的小分子已经被广泛地用于治疗和生物化学目的。超过两万个微生物培养液样品经受我们的CETP抑制剂筛选程序。最后，我们发现了来自真菌菌株的erabulenols和来自放线菌菌株的ferroverdins，作为新型CETP抑制剂。我们还观察到已知的真菌代谢产物，最初作为黄色色素分离的scleroclavin和作为弹性蛋白酶抑制剂分离的L681512化合物，抑制CETP活性。在天然来源的CETP抑制剂中，绿铁菌素B显示出非常有效的CETP抑制，具有纳摩尔IC Δ D250 Δ D2值。使用转基因小鼠显示了硬化蛋白和L681512的离体功效。

项目成果

N. Tabata, H. Tomoda, and S. Omura: "Erabulenols A and B, inhibitors cholesteryl ester transfer protein, produced by Penicillium sp. FO-5637. II.Structure elucidation of erabulenols A and B"J. Antibiot. 51. 624-628 (1998)

N. Tabata、H. Tomoda 和 S. Omura：“Erabulenols A 和 B，胆固醇酯转移蛋白抑制剂，由青霉属 sp. FO-5637 产生。II.erabulenols A 和 B 的结构阐明”J。

N.Tabata, H.Tomoda, and S.Omura: "Erabulenoles A and B, inhibitors of cholesteryl ester transfer protein, produced by Penicillium sp. FO-5637. II. Structure elucidation of erabulenols A and B"J. Anitibiot.. 51. 624-628 (1998)

N.Tabata、H.Tomoda 和 S.Omura：“Erabulenoles A 和 B，胆固醇酯转移蛋白抑制剂，由青霉属 sp. FO-5637 产生。II.erabulenoles A 和 B 的结构阐明”J。

N.Tabata,H.Tomoda,Y.Yamaguchi,R.Masuma: "Inhibition of cholesteryl ester transfer protein by fungal metabolites, L681.512"J.Antibiot.. 52. 1042-1045 (1999)

N.Tabata，H.Tomoda，Y.Yamaguchi，R.Masuma：“真菌代谢物对胆固醇酯转移蛋白的抑制，L681.512”J.Antibiot.. 52. 1042-1045 (1999)

N.Tabata, H.Tomoda,S.Omura: "Ferroverdins, Inhibitors of cholesteryl ester transfer protein produced by Streptomyces sp.WK-5344.II.Structure elucidation"J.Antibiot.. 52. 1108-1113 (1999)

N.Tabata、H.Tomoda、S.Omura：“Ferroverdins，链霉菌属 sp.WK-5344 产生的胆固醇酯转移蛋白的抑制剂。II.结构阐明”J.Antibiot.. 52. 1108-1113 (1999)

Tomoda,H., Tabata,N., et al.: "Erabulenoles A and B, inhibitors of cholesteryl ester transfer protein, produced by Penicillium sp. FO-5637. II. Structure elucidation of erabulenoles A and B" J.Antibiot. 51. 624-628 (1998)

Tomoda,H., Tabata,N., et al.：“Erabulenoles A 和 B，胆固醇酯转移蛋白抑制剂，由青霉属 sp. FO-5637 产生。II.erabulenoles A 和 B 的结构阐明”J.Antibiot。