Screening for inhibitors of Cholesteryl Ester Transfer Protein

Cholesteryl ester transfer protein （CETP） promotes exchange and transfer of neutral lipids such as cholesteryl ester （CE） and TG between plasma lipoproteins。证据已经累积了CETP在动脉粥样硬化中的重要性。因此，对CETP的抑制被提议作为一个新颖的目标来实现抗动脉粥样硬化药物。有趣的是，CETP介导的脂质转移机制仍然不清楚。在事实上，小分子调制CETP活动已被广泛搜寻以促进治疗和生物化学用途，超过2000个微文化兄弟的样本被提交给CETP抑制剂的筛选程序。最后，我们发现了来自真菌神经系的Erabulenol和来自活性细胞系的Ferroverdin，作为一种新颖的CETP抑制剂。我们也观察到已知的真菌代谢物， sclerotiorin原始分离为黄色颜料和L 681512化合物分离为弹性酶抑制剂和抑制CETP活动。从模型反应中， sclerotiorin可以与一种初级胺反应，如N末端半胱氨酸和/或赖氨酸在CETP分子中形成一种结合键。Among CETP inhibitors of natural origin ferroverdin B show very potent CETP inhibition with a nanomolar ICイイD250イエD2 value。体外效应被用来显示转基因老鼠用于Sclerotiorin和L 681512。

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.