The HIV-1 envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4- and CCR5-bound) and postfusion states to facilitate HIV-1 entry into cells. Although the prefusion closed conformation is a potential target for inhibition, development of small-molecule leads has been stymied by difficulties in obtaining structural information. Here, we report crystal structures at 3.8-Å resolution of an HIV-1-Env trimer with BMS-378806 and a derivative BMS-626529 for which a prodrug version is currently in Phase III clinical trials. Both lead candidates recognized an induced binding pocket that was mostly excluded from solvent and comprised of Env elements from a conserved helix and the β20–21 hairpin. In both structures, the β20–21 region assumed a conformation distinct from prefusion-closed and CD4-bound states. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms by which these small-molecule leads inhibit CD4-induced structural changes in Env.

中文翻译：

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具有进入抑制剂 BMS-378806 和 BMS-626529 的三聚体 HIV 包膜的晶体结构

HIV-1 包膜 (Env) 刺突是一种构象机器，可在融合前（闭合、CD4 和 CCR5 结合）和融合后状态之间转换，以促进 HIV-1 进入细胞。尽管预融合闭合构象是抑制的潜在目标，但小分子先导化合物的开发因难以获得结构信息而受到阻碍。在这里，我们报告了 HIV-1-Env 三聚体与 BMS-378806 和衍生物 BMS-626529 的 3.8-Å 分辨率晶体结构，其前药版本目前正在进行 III 期临床试验。两个主要候选者都识别出诱导结合袋，该结合袋大部分被排除在溶剂之外，并且由来自保守螺旋和 β20-21 发夹的 Env 元件组成。在这两种结构中，β20-21 区域呈现出与融合前闭合状态和 CD4 结合状态不同的构象。结合生物物理和抗原性特征，这些结构阐明了这些小分子先导物抑制 CD4 诱导的 Env 结构变化的变构和竞争机制。