Addressing Antiretroviral Drug Resistance with Host-Targeting Drugs-First Steps towards Developing a Host-Targeting HIV-1 Assembly Inhibitor.
Addressing Antiretroviral Drug Resistance with Host-Targeting Drugs-First Steps towards Developing a Host-Targeting HIV-1 Assembly Inhibitor.
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DOI：
10.3390/v13030451
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发表时间：
2021-03-10
期刊：
影响因子：
--
通讯作者：
Reed JC
中科院分区：
文献类型：
--
作者：
Lingappa JR;Lingappa VR;Reed JC
HIV-1耐药性的增加令人担忧，这表明应优先开发靶向宿主的抗病毒药物，因为此类药物可以为耐药病毒变体的选择提供高遗传屏障。靶向宿主蛋白质还可以产生作用于病毒生命周期事件的药物，这些事件已被证明难以抑制，例如HIV-1未成熟衣壳组装的细胞内事件。在这里，我们回顾了主要通过HIV-1自组装筛选确定的小分子抑制剂，并描述了所有这些抑制剂如何在进入后狭窄或广泛地作用于HIV-1生命周期的早期和晚期事件。我们建议，一种不同的筛选方法可以识别化合物，特异性抑制HIV-1 Gag组装，观察到一个有效的狂犬病病毒抑制剂时，使用主机催化的狂犬病组装屏幕。作为这种可能性的一个例子，我们讨论了最近使用筛选鉴定的一种抗逆转录病毒小分子，该分子概括了宿主催化的HIV-1衣壳组装途径。这种化学型通过特异性抑制不成熟的HIV-1衣壳组装而有效地阻断HIV-1在T细胞中的复制，但在37代以上未能选择抗性病毒变体，这表明宿主蛋白质靶标。这种小分子的开发可以产生新的宿主靶向抗逆转录病毒药物，并提供对这些药物靶向的宿主机制失调引起的慢性疾病的深入了解。
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.
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DOI：
10.1038/nrmicro3503
发表时间：
2015-08
期刊：
Nature reviews. Microbiology
影响因子：
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作者：
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通讯作者：
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影响因子：
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10.1146/annurev-virology-092917-043448
发表时间：
2018-01-01
期刊：
ANNUAL REVIEW OF VIROLOGY, VOL 5
影响因子：
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通讯作者：
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DOI：
10.1073/pnas.1419945112
发表时间：
2014-12-30
影响因子：
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作者：
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通讯作者：
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