Of the targets for HIV-1 therapeutics, the capsid core is a relatively unexploited but alluring drug target due to its indispensable roles throughout virus replication. Because of this, we aimed to identify “clickable” covalent modifiers of the HIV-1 capsid protein (CA) for future functionalization. We screened a library of fluorosulfate compounds that can undergo sulfur(VI) fluoride exchange (SuFEx) reactions, and five compounds were identified as hits. These molecules were further characterized for antiviral effects. Several compounds impacted capsid assembly. One compound, BBS-103, covalently bound CA via a SuFEx reaction to Tyr145 and had antiviral activity in cell-based assays by perturbing virus production, but not uncoating. The covalent binding of compounds that target the HIV-1 capsid could aid in the future design of antiretroviral drugs or chemical probes that will help study aspects of HIV-1 replication.

中文翻译：

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鉴定可点击的 HIV-1 衣壳靶向探针以抑制病毒复制

在 HIV-1 治疗的靶标中，衣壳核心是一个相对未开发但有吸引力的药物靶标，因为它在病毒复制过程中发挥着不可或缺的作用。因此，我们的目标是识别 HIV-1 衣壳蛋白 (CA) 的“可点击”共价修饰剂，以用于未来的功能化。我们筛选了可以进行六氟化硫交换 (SuFEx) 反应的氟代硫酸盐化合物库，并确定了五种化合物为命中化合物。这些分子的抗病毒作用得到了进一步的表征。几种化合物影响衣壳组装。一种化合物 BBS-103 通过 SuFEx 反应与 Tyr145 共价结合 CA，并在基于细胞的测定中通过扰乱病毒产生而不是脱壳而具有抗病毒活性。针对 HIV-1 衣壳的化合物的共价结合可能有助于未来抗逆转录病毒药物或化学探针的设计，从而有助于研究 HIV-1 复制的各个方面。