Advances in structure-activity relationships of HDAC inhibitors as HIV latency-reversing agents.

IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Expert Opinion on Drug Discovery Pub Date : 2024-03-01 Epub Date: 2024-01-23 DOI:10.1080/17460441.2024.2305730
Samima Khatun, Sk Abdul Amin, Debasmita Choudhury, Boby Chowdhury, Tarun Jha, Shovanlal Gayen
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Abstract

Introduction: HIV-infected cells may rebound due to the existence of the silent HIV-infected memory CD4+ T cells (HIV latency). This HIV latency makes the disease almost incurable. In latency, the integrated proviral DNA of HIV is transcriptionally silenced partly due to the activity of histone deacetylases (HDACs). Hence, inhibition of HDAC is considered a prime target for HIV latency reversal.

Areas covered: A brief biology and function of HDACs have been discussed to identify key points to design HDAC inhibitors (HDACis). This article summarizes recent achievements in the development of HDACis to achieve HIV latency reversal. Structure-activity relationships (SARs) of some series of compounds were also explored.

Expert opinion: Depletion of the HIV reservoir is the only way to end this deadly epidemic. HDACis are latency-reversing agents (LRA) that can be used to 'shock' the latently infected CD4+ T cells to induce them to produce viral proteins. It is interesting to note that HDAC3, which is extensively expressed in resting T cells, is specifically preferred by benzamide-containing HDACis for inhibition. Thus, the benzamide class of compounds should be explored. Nevertheless, more data on selective HDAC inhibition is needed for further development of HDACis in HIV latency reversal.

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作为艾滋病潜伏期逆转剂的 HDAC 抑制剂的结构-活性关系研究进展。
导言:由于存在沉默的艾滋病毒感染记忆 CD4+ T 细胞(艾滋病毒潜伏期),艾滋病毒感染细胞可能会反弹。这种艾滋病病毒潜伏期使这种疾病几乎无法治愈。在潜伏期,HIV 的整合前病毒 DNA 在转录上处于沉默状态,部分原因是组蛋白去乙酰化酶(HDAC)的活性。因此,抑制 HDAC 被认为是逆转 HIV 潜伏期的主要目标:本文简要讨论了 HDAC 的生物学特性和功能,以确定设计 HDAC 抑制剂(HDACis)的关键点。本文总结了最近在开发HDACis以逆转HIV潜伏期方面取得的成就。同时还探讨了一些系列化合物的结构-活性关系(SARs):耗尽艾滋病病毒库是结束这一致命流行病的唯一途径。HDACis 是一种潜伏逆转剂 (LRA),可用于 "冲击 "潜伏感染的 CD4+ T 细胞,诱导它们产生病毒蛋白。值得注意的是,静息 T 细胞中广泛表达的 HDAC3 特别容易被含苯甲酰胺的 HDACis 抑制。因此,应探索苯甲酰胺类化合物。不过,还需要更多关于选择性 HDAC 抑制的数据,以进一步开发用于逆转 HIV 潜伏期的 HDACis。
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来源期刊
CiteScore
10.20
自引率
1.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Expert Opinion on Drug Discovery (ISSN 1746-0441 [print], 1746-045X [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on novel technologies involved in the drug discovery process, leading to new leads and reduced attrition rates. Each article is structured to incorporate the author’s own expert opinion on the scope for future development. The Editors welcome: Reviews covering chemoinformatics; bioinformatics; assay development; novel screening technologies; in vitro/in vivo models; structure-based drug design; systems biology Drug Case Histories examining the steps involved in the preclinical and clinical development of a particular drug The audience consists of scientists and managers in the healthcare and pharmaceutical industry, academic pharmaceutical scientists and other closely related professionals looking to enhance the success of their drug candidates through optimisation at the preclinical level.
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