Institut de Recherche en Infectiologie de Montpellier (IRIM), University of Montpellier, CNRS 9004, 34293, Montpellier, France.
Department of Virology, INSERM, Sorbonne University, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
EMBO Mol Med. 2024 Nov;16(11):2918-2945. doi: 10.1038/s44321-024-00143-w. Epub 2024 Oct 2.
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 IC. 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.
HIV-1 衣壳通过与核输入机制结合来穿越核孔复合体 (NPC)。为了鉴定抑制 HIV-1 核输入的化合物，我们在结合 Transportin-1 (TRN-1) 的 CA 六聚体的三维模型上对药物进行了计算机筛选。在命中化合物中，化合物 H27 以低微摩尔 IC 抑制 HIV-1。与其他 CA 靶向化合物不同，H27 不会改变 CA 的组装或拆卸，特异性抑制核输入，并保留对 PF74-和 Lenacapavir 耐药突变体的抗病毒活性。不同灵长类慢病毒衣壳的敏感性差异、衣壳稳定性和 H27 逃逸突变体，以及结构分析表明，H27 与组装好的衣壳形成多个低亲和力接触点。相互作用实验表明，H27 可能通过阻止 CA 与 NPC 机制的成分（如 TRN-1）结合来发挥作用。H27 在体内表现出良好的代谢稳定性，对来自未经治疗的患者的不同亚型和循环重组形式以及对四种主要类别的抗逆转录病毒药物耐药的菌株均有效。这项工作鉴定了通过特异性阻断 HIV-1 核输入来发挥作用的化合物，它们具有一种新的作用机制。
