基于结构的新型二氢烷氧基苄氧基嘧啶衍生物设计，作为人类免疫缺陷病毒逆转录酶的有效非核苷抑制剂。
Structure-based design of novel dihydroalkoxybenzyloxopyrimidine derivatives as potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase.
作者信息
Sudbeck E A, Mao C, Vig R, Venkatachalam T K, Tuel-Ahlgren L, Uckun F M
机构信息
Drug Discovery Program, Hughes Institute, St. Paul, Minnesota 55113, USA.
出版信息
Antimicrob Agents Chemother. 1998 Dec;42(12):3225-33. doi: 10.1128/AAC.42.12.3225.
Abstract
Two highly potent dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of human immunodeficiency virus (HIV) reverse transcriptase (RT) have been designed based on the structure of the NNI binding pocket and tested for anti-HIV activity. Our lead DABO derivative, 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-on e, elicited potent inhibitory activity against purified recombinant HIV RT and abrogated HIV replication in peripheral blood mononuclear cells at nanomolar concentrations (50% inhibitory concentration, <1 nM) but showed no detectable cytotoxicity at concentrations as high as 100 microM.
摘要
基于非核苷抑制剂（NNI）结合口袋的结构，设计了两种靶向人类免疫缺陷病毒（HIV）逆转录酶（RT）的NNI结合位点的高效二氢烷氧基苄氧基嘧啶（DABO）衍生物，并对其抗HIV活性进行了测试。我们的先导DABO衍生物5-异丙基-2-[(甲硫基甲基)硫基]-6-(苄基)-嘧啶-4-(1H)-酮，对纯化的重组HIV RT具有强效抑制活性，并在纳摩尔浓度（50%抑制浓度，<1 nM）下消除外周血单个核细胞中的HIV复制，但在高达100 μM的浓度下未显示出可检测到的细胞毒性。
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