甲型流感病毒血凝素:从经典的融合抑制剂到基于蛋白水解靶向嵌合体的抗病毒药物研发策略

Francisco Javier Hermoso-Pinilla, Aitor Valdivia, M. Camarasa, Tiziana Ginex, F. J. Luque
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摘要

流感病毒糖蛋白血凝素(HA)参与病毒颗粒附着到宿主细胞膜受体和膜融合的关键步骤。由于其在甲型流感感染初期阶段的关键作用,HA 成为了寻找新型候选药物的一个有希望的靶点。鉴于 HA 在甲型流感感染早期阶段的关键作用,过去几十年来,针对 HA 的药物研发工作一直在紧张进行。药物发现研究主要依赖于阻止球头(GH)结构域中的受体结合位点识别硅酸单位,或阻止病毒与细胞膜融合所需的构象重排。本研究旨在总结 HA 靶向开发小分子融合抑制剂的进展。为此,我们将主要关注与融合抑制剂结合的 HA 的 X 射线晶体学结构分析。此外,本研究还将重点介绍在利用结构信息和分子建模技术方面所做的努力,以揭示融合抑制剂的作用机制,并协助设计和解释新型先导化合物的结构-活性关系。最后一部分将专门阐明新颖而有前途的抗病毒策略,这些策略源于将已知的小分子抗病毒药物转化为基于蛋白水解靶向嵌合体(PROTAC)的靶向蛋白降解。这些知识将有助于利用基于结构的经典和新型抗病毒策略,同时加深对作用机制的理解,并最大限度地减少耐药性的影响。
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Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery
The influenza virus glycoprotein hemagglutinin (HA) participates in critical steps of the attachment of viral particles to the host cell membrane receptor and membrane fusion. Due to its crucial involvement in the initial phases of influenza A infections, HA emerges as a promising target in the search of novel drug-like candidates. Given its pivotal role in the early stages of influenza A infections, intense drug discovery efforts have been undertaken to target HA in the past decades. Drug discovery studies mainly rely on preventing the recognition of sialic acid units by the receptor binding site in the globular head (GH) domain, or the conformational rearrangement required for the fusion of viral and cell membranes. In this work, the aim is to summarize the progress made in HA-targeted development of small molecule fusion inhibitors. To this end, attention will primarily be focused on the analysis of the X-ray crystallographic structures of HA bound to fusion inhibitors. Furthermore, this study also aims to highlight the efforts made in exploiting the structural information in conjunction with molecular modeling techniques to discern the mechanism of action of the fusion inhibitors and to assist the design and interpretation of structure-activity relationships of novel lead compounds will be highlighted. The final section will be dedicated to elucidating novel and promising antiviral strategies proceeding from the transformation of known small molecule antivirals in proteolysis targeting chimera (PROTAC)-based targeted protein degradation. This knowledge will be valuable to assist the exploitation of classical and novel antiviral structure-based strategies, together with a deeper understanding of the mechanism of action and minimization of the impact of drug resistance.
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