Targeting the open-flap conformation of HIV-1 protease with pyrrolidine-based inhibitors
Targeting the open-flap conformation of HIV-1 protease with pyrrolidine-based inhibitors
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DOI：
10.1002/cmdc.200800113
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发表时间：
2008-09-01
期刊：
影响因子：
3.4
通讯作者：
Klebe, Gerhard
中科院分区：
文献类型：
--
作者：
Boettcher, Jark;Blum, Andreas;Klebe, Gerhard
HIV蛋白酶是抗病毒化疗中公认的药物靶点。人们已经做出了巨大的研究努力来发现有效的抑制剂，从而使该酶成为研究最多、特征最好的蛋白质之一。尽管该酶表现出很高的柔韧性，但所有批准的药物实际上都是针对某些蛋白质构象的。病毒交叉耐药性的发展需要产生具有新型支架的抑制剂。和背离的捆绑方式。在这里，我们报道了一系列针对蛋白水解酶开瓣构象的手性、对称的吡咯烷类抑制剂的设计和短、高产率的立体选择性合成。得到的一种衍生物的共晶结构为进一步的缓蚀剂设计提供了有价值的起点。
HIV protease is a well-established drug target in antiviral chemotherapy. Immense research efforts have been made to discover effective inhibitors, thus making the enzyme one of the most studied and best characterized proteins. Although the protease exhibits high flexibility, all approved drugs target virtually the some protein conformation. The development of viral cross-resistance demands the generation of inhibitors with novel, scaffolds. and deviating modes of binding. Herein we report the design and the short, high-yielding stereoselective synthesis of a series of chiral, symmetric pyrrolidine-based inhibitors targeting the open-flap conformation of the protease. The obtained co-crystal structure with one derivative provides a valuable starting point for further inhibitor design.