Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre- and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.

中文翻译：

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副粘病毒和肺病毒进入抑制的结构洞察。


副粘病毒和肺病毒通过融合 (F) 蛋白介导的病毒包膜与靶膜的合并来感染细胞。这些家族的成员包括一系列主要的人类和动物病原体，例如呼吸道合胞病毒（RSV）、麻疹病毒（MeV）、人类副流感病毒（HPIV）和高致病性尼帕病毒（NiV）。该家族的多个成员已经解决了融合前和融合后构象的高分辨率 F 蛋白结构，并且许多 F 靶向进入抑制剂已进入高级开发或临床测试阶段。然而，小分子 RSV 进入抑制剂在临床试验中总体上令人失望，并且病毒耐药性在实验环境和患者中迅速发展，引发了一个问题：现有的结构信息是否可以提供一条通过主动抑制剂工程来抵消病毒逃逸的途径。本文将总结当前对 F 介导的膜融合的机制见解，并研究结构信息对小分子 F 抑制剂开发的贡献。概述了对未来药物靶点选择和合理药物工程策略的影响。