Department of Global Health, University of Washington, Seattle, WA 98109, USA.
Prosetta Biosciences, 670 5th Street, San Francisco, CA 94107, USA.
Viruses. 2021 Mar 10;13(3):451. doi: 10.3390/v13030451.
The concerning increase in HIV-1 resistance argues for prioritizing the development of host-targeting antiviral drugs because such drugs can offer high genetic barriers to the selection of drug-resistant viral variants. Targeting host proteins could also yield drugs that act on viral life cycle events that have proven elusive to inhibition, such as intracellular events of HIV-1 immature capsid assembly. Here, we review small molecule inhibitors identified primarily through HIV-1 self-assembly screens and describe how all act either narrowly post-entry or broadly on early and late events of the HIV-1 life cycle. We propose that a different screening approach could identify compounds that specifically inhibit HIV-1 Gag assembly, as was observed when a potent rabies virus inhibitor was identified using a host-catalyzed rabies assembly screen. As an example of this possibility, we discuss an antiretroviral small molecule recently identified using a screen that recapitulates the host-catalyzed HIV-1 capsid assembly pathway. This chemotype potently blocks HIV-1 replication in T cells by specifically inhibiting immature HIV-1 capsid assembly but fails to select for resistant viral variants over 37 passages, suggesting a host protein target. Development of such small molecules could yield novel host-targeting antiretroviral drugs and provide insight into chronic diseases resulting from dysregulation of host machinery targeted by these drugs.
HIV-1 耐药性的令人担忧的增加表明，优先开发针对宿主的抗病毒药物是必要的，因为此类药物可以为耐药病毒变异体的选择提供高遗传屏障。针对宿主蛋白的药物也可以作用于那些对抑制具有挑战性的病毒生命周期事件，例如 HIV-1 不成熟衣壳组装的细胞内事件。在这里，我们主要通过 HIV-1 自我组装筛选鉴定了小分子抑制剂，并描述了它们如何在进入后或广泛地作用于 HIV-1 生命周期的早期和晚期事件。我们提出，一种不同的筛选方法可以识别出特异性抑制 HIV-1 Gag 组装的化合物，就像使用宿主催化的狂犬病组装筛选鉴定出一种有效的狂犬病病毒抑制剂时所观察到的那样。作为这种可能性的一个例子，我们讨论了最近使用一种重现宿主催化的 HIV-1 衣壳组装途径的筛选方法鉴定出的一种抗逆转录病毒小分子。这种化学型通过特异性抑制不成熟的 HIV-1 衣壳组装，有效地阻断 T 细胞中的 HIV-1 复制，但在 37 个传代中未能选择出耐药的病毒变异体，这表明存在一个宿主蛋白靶点。这类小分子的开发可能会产生新的针对宿主的抗逆转录病毒药物，并深入了解这些药物靶向的宿主机制失调所导致的慢性疾病。
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