Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
Antiviral Res. 2010 Jan;85(1):101-18. doi: 10.1016/j.antiviral.2009.11.004. Epub 2009 Nov 17.
HIV-1 integrase (IN) is one of three essential enzymes (along with reverse transcriptase and protease) encoded by the viral pol gene. IN mediates two critical reactions during viral replication; firstly 3'-end processing (3'EP) of the double-stranded viral DNA ends and then strand transfer (STF) which joins the viral DNA to the host chromosomal DNA forming a functional integrated proviral DNA. IN is a 288 amino acid protein containing three functional domains, the N-terminal domain (NTD), catalytic core domain (CCD) and the C-terminal domain (CTD). The CCD contains three conserved catalytic residues, Asp64, Asp116 and Glu152, which coordinate divalent metal ions essential for the STF reaction. Intensive research over the last two decades has led to the discovery and development of small molecule inhibitors of the IN STF reaction (INSTIs). INSTIs are catalytic inhibitors of IN, and act to chelate the divalent metal ions in the CCD. One INSTI, raltegravir (RAL, Merck Inc.) was approved in late 2007 for the treatment of HIV-1 infection in patients with prior antiretroviral (ARV) treatment experience and was recently approved also for first line therapy. A second INSTI, elvitegravir (EVG, Gilead Sciences, Inc.) is currently undergoing phase 3 studies in ARV treatment-experienced patients and phase 2 studies in ARV naïve patients as part of a novel fixed dose combination. Several additional INSTIs are in early stage clinical development. This review will discuss the discovery and development of this novel class of antiretrovirals. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.
HIV-1 整合酶（IN）是病毒 pol 基因编码的三种必需酶（逆转录酶和蛋白酶）之一。IN 在病毒复制过程中介导两个关键反应；首先是双链病毒 DNA 末端的 3'-末端加工（3'EP），然后是链转移（STF），将病毒 DNA 与宿主染色体 DNA 连接形成功能性整合前病毒 DNA。IN 是一种由 288 个氨基酸组成的蛋白质，包含三个功能域，即 N 端结构域（NTD）、催化核心结构域（CCD）和 C 端结构域（CTD）。CCD 包含三个保守的催化残基，天冬氨酸 64、天冬氨酸 116 和谷氨酸 152，它们协调参与 STF 反应的二价金属离子。过去二十年的深入研究导致了 IN STF 反应（INSTIs）的小分子抑制剂的发现和开发。INSTIs 是 IN 的催化抑制剂，作用是螯合 CCD 中的二价金属离子。一种 INSTI，raltegravir（RAL，默克公司）于 2007 年末获准用于治疗有既往抗逆转录病毒（ARV）治疗经验的 HIV-1 感染患者，并最近也获准用于一线治疗。第二种 INSTI，elvitegravir（EVG，吉利德科学公司）目前正在接受 ARV 治疗经验丰富的患者的 3 期研究和 ARV 初治患者的 2 期研究，作为新型固定剂量联合治疗的一部分。还有几种其他的 INSTIs 处于早期临床开发阶段。这篇综述将讨论这一类新型抗逆转录病毒药物的发现和开发。本文是抗病毒研究杂志 25 周年纪念特刊的一部分，该特刊纪念抗逆转录病毒药物发现和开发 25 周年，第 85 卷，第 1 期，2010 年。
