Computer-Aided Approaches for Targeting HIVgp41.
Computer-Aided Approaches for Targeting HIVgp41.
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DOI：
10.3390/biology1020311
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发表时间：
2012-08-20
期刊：
影响因子：
4.2
通讯作者：
Rizzo RC
中科院分区：
文献类型：
--
作者：
Allen WJ;Rizzo RC
病毒-细胞融合是人类免疫缺陷病毒 1 (HIV) 将其遗传物质传递到人类 T 细胞宿主的主要方式。融合在很大程度上是由病毒糖蛋白 41 (gp41) 介导的，病毒糖蛋白 41 (gp41) 通过四种不同的构象状态前进：(i) 天然、(ii) 发夹前中间体、(iii) 融合活性（融合）和 (iv) 融合后。鉴于 gp41 N 端七肽重复序列 (NHR) 和 C 端七肽重复序列 (CHR) 结构域在形成融合所需的六螺旋束之前短暂暴露，前发夹中间体对于治疗干预来说是一个特别有吸引力的步骤。大多数基于肽的抑制剂，包括 FDA 批准的药物 T20，都以中间体为目标，并且正在努力开发小分子替代品。在这里，我们回顾了当前研究抑制剂与 gp41 相互作用的方法，重点是原子级计算机建模方法，包括分子动力学、自由能分析和对接。原子模型产生了独特水平的结构和能量细节，与实验方法相辅相成，这对于改进的下一代抗艾滋病毒药物的设计非常重要。
Virus-cell fusion is the primary means by which the human immunodeficiency virus-1 (HIV) delivers its genetic material into the human T-cell host. Fusion is mediated in large part by the viral glycoprotein 41 (gp41) which advances through four distinct conformational states: (i) native, (ii) pre-hairpin intermediate, (iii) fusion active (fusogenic), and (iv) post-fusion. The pre-hairpin intermediate is a particularly attractive step for therapeutic intervention given that gp41 N-terminal heptad repeat (NHR) and C‑terminal heptad repeat (CHR) domains are transiently exposed prior to the formation of a six-helix bundle required for fusion. Most peptide-based inhibitors, including the FDA‑approved drug T20, target the intermediate and there are significant efforts to develop small molecule alternatives. Here, we review current approaches to studying interactions of inhibitors with gp41 with an emphasis on atomic-level computer modeling methods including molecular dynamics, free energy analysis, and docking. Atomistic modeling yields a unique level of structural and energetic detail, complementary to experimental approaches, which will be important for the design of improved next generation anti-HIV drugs.