Discovery and analysis of inhibitors of the human immunodeficiency integrase.

Drug design and discovery Pub Date : 1997-05-01
D Hazuda, P J Felock, J C Hastings, B Pramanik, A L Wolfe
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Abstract

An essential step in the replication of retroviruses is the integration of a DNA copy of the viral genome into the genome of the host cell. Integration encompasses a series of ordered endonucleolytic and DNA strand transfer reactions catalyzed by the viral enzyme, integrase. The requirement for integrase activity in the propagation of HIV-1 in cell culture defines the enzyme as a potential target for chemotherapeutic intervention. We have therefore developed a non-radioisotopic microtiter plate assay which can be used to identify novel inhibitors of integrase from random chemical screens and for the bioassay driven isolation of inhibitors from natural products. This assay uncouples various steps in the reaction pathway and therefore can be exploited to characterize inhibitors. In this monograph we describe a series of modifications to the method which facilitate such mechanistic studies using as an example a series of previously described integrase inhibitors.

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人类免疫缺陷整合酶抑制剂的发现和分析。
逆转录病毒复制的一个重要步骤是将病毒基因组的DNA拷贝整合到宿主细胞的基因组中。整合包括一系列有序的核内分解和DNA链转移反应,由病毒酶,整合酶催化。细胞培养中HIV-1的繁殖对整合酶活性的要求将该酶定义为化疗干预的潜在靶点。因此,我们开发了一种非放射性同位素微滴板测定法,可用于从随机化学筛选中识别整合酶的新型抑制剂,并用于从天然产物中分离抑制剂的生物测定。该分析在反应途径中解耦的各个步骤,因此可以用来表征抑制剂。在本专著中,我们描述了一系列修改的方法,以促进这种机制的研究,使用作为一个例子,一系列先前描述的整合酶抑制剂。
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