Novel Histone Deacetylase Inhibitors and HIV-1 Latency-Reversing Agents Identified by Large-Scale Virtual Screening
Novel Histone Deacetylase Inhibitors and HIV-1 Latency-Reversing Agents Identified by Large-Scale Virtual Screening
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DOI：
10.3389/fphar.2020.00905
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发表时间：
2020-06-17
影响因子：
5.6
通讯作者：
Tietjen, Ian
中科院分区：
文献类型：
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作者：
Divsalar, Donya Naz;Simoben, Conrad Veranso;Tietjen, Ian
目前用于艾滋病毒管理的抗逆转录病毒疗法并不针对人类潜伏的病毒库。这种实验性的“休克-杀伤”治疗方法包括使用潜伏逆转剂（LRAs）重新激活含有HIV的细胞中的HIV表达，然后通过病毒或宿主免疫细胞病变作用消除受感染的细胞。据报道，一些LRAs作为组蛋白去乙酰化酶（HDAC）抑制剂在细胞和临床试验中逆转HIV潜伏期；然而，到目前为止，还没有一种能够持续减少人类的病毒储存库，这促使人们需要识别新的LRAs。为了实现这一目标，我们在这里描述了一种虚拟筛选（VS）方法，该方法使用14种已报道的HDAC抑制剂来探测PubChem并确定60个LRA候选物。然后，我们展示了四种筛选“hit”，包括(S)-N- N-羟基-4-（3-甲基-2-苯基丁烷酰胺）苯甲酰胺（化合物15），N-（4-氨基苯基）庚烷酰胺（16），N-[4-（庚氨基）苯基]庚烷酰胺（17）和4-（1,3-二氧基- 1h -苯并[de]异喹啉-2(3H)-基）-N-（2-羟乙基）丁烷酰胺（18），抑制HDAC活性和/或逆转HIV体外潜伏期。这项研究证明并支持基于vs的方法可以很容易地识别新的HDAC抑制剂和LRAs，这反过来可能有助于抑制剂设计和化学优化工作，以改进基于HIV的休克和杀伤工作。
Current antiretroviral therapies used for HIV management do not target latent viral reservoirs in humans. The experimental "shock-and-kill" therapeutic approach involves use of latency-reversal agents (LRAs) that reactivate HIV expression in reservoir-containing cells, followed by infected cell elimination through viral or host immune cytopathic effects. Several LRAs that function as histone deacetylase (HDAC) inhibitors are reported to reverse HIV latency in cells and in clinical trials; however, none to date have consistently reduced viral reservoirs in humans, prompting a need to identify new LRAs. Toward this goal, we describe here a virtual screening (VS) approach which uses 14 reported HDAC inhibitors to probe PubChem and identifies 60 LRA candidates. We then show that four screening "hits" including (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide (compound15),N-(4-Aminophenyl)heptanamide (16),N-[4-(Heptanoylamino)phenyl]heptanamide (17), and 4-(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-N-(2-hydroxyethyl)butanamide (18) inhibit HDAC activity and/or reverse HIV latencyin vitro. This study demonstrates and supports that VS-based approaches can readily identify novel HDAC inhibitors and LRAs, which in turn may help toward inhibitor design and chemical optimization efforts for improved HIV shock-and-kill-based efforts.