Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Biochem J. 2010 Aug 1;429(3):527-32. doi: 10.1042/BJ20091645.
Clinically approved inhibitors of the HIV-1 protease function via a competitive mechanism. A particular vulnerability of competitive inhibitors is their sensitivity to increases in substrate concentration, as may occur during virion assembly, budding and processing into a mature infectious viral particle. Advances in chemical synthesis have led to the development of new high-diversity chemical libraries using rapid in-solution syntheses. These libraries have been shown previously to be effective at disrupting protein-protein and protein-nucleic acid interfaces. We have screened 44000 compounds from such a library to identify inhibitors of the HIV-1 protease. One compound was identified that inhibits wild-type protease, as well as a drug-resistant protease with six mutations. Moreover, analysis of this compound suggests an allosteric non-competitive mechanism of inhibition and may represent a starting point for an additional strategy for anti-retroviral therapy.
临床上已批准的 HIV-1 蛋白酶抑制剂通过竞争性机制发挥作用。竞争性抑制剂的一个特殊弱点是它们对底物浓度增加的敏感性，这种情况可能发生在病毒体组装、出芽和加工成成熟感染性病毒颗粒的过程中。化学合成技术的进步使得使用快速溶液合成法开发了新的高多样性化学文库成为可能。此前已经证明，这些文库在破坏蛋白质-蛋白质和蛋白质-核酸界面方面非常有效。我们已经从这样的文库中筛选了 44000 种化合物，以鉴定 HIV-1 蛋白酶抑制剂。已经鉴定出一种化合物可抑制野生型蛋白酶以及具有六种突变的耐药性蛋白酶。此外，对该化合物的分析表明，它的抑制机制是变构非竞争性，这可能为抗逆转录病毒治疗提供另一种策略的起点。
