HIV-1 capsids cross nuclear pore complexes (NPCs) by engaging with the nuclear import machinery. To identify compounds that inhibit HIV-1 nuclear import, we screened drugs in silico on a three-dimensional model of a CA hexamer bound by Transportin-1 (TRN-1). Among hits, compound H27 inhibited HIV-1 with a low micromolar IC50. Unlike other CA-targeting compounds, H27 did not alter CA assembly or disassembly, inhibited nuclear import specifically, and retained antiviral activity against PF74- and Lenacapavir-resistant mutants. The differential sensitivity of divergent primate lentiviral capsids, capsid stability and H27 escape mutants, together with structural analyses, suggest that H27 makes multiple low affinity contacts with assembled capsid. Interaction experiments indicate that H27 may act by preventing CA from engaging with components of the NPC machinery such as TRN-1. H27 exhibited good metabolic stability in vivo and was efficient against different subtypes and circulating recombinant forms from treatment-naïve patients as well as strains resistant to the four main classes of antiretroviral drugs. This work identifies compounds that demonstrate a novel mechanism of action by specifically blocking HIV-1 nuclear import.

中文翻译：

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一类新型衣壳靶向抑制剂，专门阻断 HIV-1 核输入。


HIV-1 衣壳通过与核输入机制接触穿过核孔复合体 （NPC）。为了鉴定抑制 HIV-1 核输入的化合物，我们在 Transportin-1 （TRN-1） 结合的 CA 六聚体的三维模型上用计算机筛选了药物。在命中中，化合物 H27 抑制 HIV-1 且微摩尔 IC50 较低。与其他靶向 CA 的化合物不同，H27 不会改变 CA 的组装或分解，特异性地抑制核输入，并保留对 PF74 和 Lenacapavir 耐药突变体的抗病毒活性。不同的灵长类动物慢病毒衣壳、衣壳稳定性和 H27 逃逸突变体的敏感性差异，以及结构分析表明，H27 与组装的衣壳进行多次低亲和力接触。相互作用实验表明，H27 可能通过阻止 CA 与 TRN-1 等 NPC 机制的组成部分啮合而发挥作用。H27 在体内表现出良好的代谢稳定性，对初治患者的不同亚型和循环重组形式以及对四大类抗逆转录病毒药物耐药的菌株有效。这项工作确定了通过特异性阻断 HIV-1 核输入来证明新作用机制的化合物。