Histone deacetylase inhibitors containing a benzamide functional group and a pyridyl cap are preferentially effective human immunodeficiency virus-1 latency-reversing agents in primary resting CD4+ T cells.
Histone deacetylase inhibitors containing a benzamide functional group and a pyridyl cap are preferentially effective human immunodeficiency virus-1 latency-reversing agents in primary resting CD4+ T cells.
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DOI：
10.1099/jgv.0.000716
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Dougherty JP
中科院分区：
文献类型：
--
作者：
Kobayashi Y;Gélinas C;Dougherty JP
抗逆转录病毒治疗 (ART) 可以控制感染个体中人类免疫缺陷病毒 1 (HIV-1) 的复制。不幸的是，由于潜伏感染的建立，患者仍然持续感染，需要无限期地维持抗逆转录病毒治疗。正在采取的一项策略是开发潜伏期逆转剂（LRAs）来消除潜伏感染。已测试 LRA 活性的一类分子是表观遗传调节化合物组蛋白脱乙酰酶抑制剂 (HDACis)。此前，这些分子的初步筛选通常是使用已建立的病毒潜伏期细胞模型开始的，尽管某些药物（例如 HDACi 辛二酰苯胺异羟肟酸）在这些模型中表现出很强的活性，但它并没有转化为与患者样本相当的活性。在这里，我们使用感染了 Vpx 补充的 HIV-1 的原代静息 CD4+ T 细胞开发了病毒潜伏期的原代细胞模型，并发现使用先前描述的 LRA 的激活曲线模仿了从患者样本中获得的激活曲线。该原代细胞模型用于评估 94 种表观遗传化合物。毫不奇怪，HDAC 被发现是最强的激活剂。然而，在 HDACi 类别中，最活跃、毒性最小的 LRA 含有带有吡啶基帽基团的苯甲酰胺功能部分，如 HDACi chidamide 所示。结果表明，应考虑将具有苯甲酰胺部分和吡啶基帽基团的 HDACis 用于进一步的药物开发，以追求成功的病毒清除策略。
Antiretroviral therapy (ART) can control human immunodeficiency virus-1 (HIV-1) replication in infected individuals. Unfortunately, patients remain persistently infected owing to the establishment of latent infection requiring that ART be maintained indefinitely. One strategy being pursued involves the development of latency-reversing agents (LRAs) to eliminate the latent arm of the infection. One class of molecules that has been tested for LRA activity is the epigenetic modulating compounds histone deacetylases inhibitors (HDACis). Previously, initial screening of these molecules typically commenced using established cell models of viral latency, and although certain drugs such as the HDACi suberoylanilide hydroxamic acid demonstrated strong activity in these models, it did not translate to comparable activity with patient samples. Here we developed a primary cell model of viral latency using primary resting CD4+ T cells infected with Vpx-complemented HIV-1 and found that the activation profile using previously described LRAs mimicked that obtained with patient samples. This primary cell model was used to evaluate 94 epigenetic compounds. Not surprisingly, HDACis were found to be the strongest activators. However, within the HDACi class, the most active LRAs with the least pronounced toxicity contained a benzamide functional moiety with a pyridyl cap group, as exemplified by the HDACi chidamide. The results indicate that HDACis with a benzamide moiety and pyridyl cap group should be considered for further drug development in the pursuit of a successful viral clearance strategy.
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