Hemagglutinin Stability Determines Influenza A Virus Susceptibility to a Broad-Spectrum Fusion Inhibitor Arbidol.
Hemagglutinin Stability Determines Influenza A Virus Susceptibility to a Broad-Spectrum Fusion Inhibitor Arbidol.
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DOI：
10.1021/acsinfecdis.2c00178
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发表时间：
2022-08-12
影响因子：
5.3
通讯作者：
Ivanovic, Tijana
中科院分区：
文献类型：
--
作者：
Li, Zhenyu;Li, Tian;Liu, Meisui;Ivanovic, Tijana
关键词：
了解抗病毒抑制剂的耐药机制可以揭示靶向病毒机制的细微差别，进而改进抑制剂设计策略。阿比朵尔是一种广谱抗病毒药物，可结合并阻止三聚体甲型流感病毒（IAV）血凝素（HA）中的融合相关构象变化。HA介导的膜融合过程中的限速步骤是疏水性融合肽从HA上的保守口袋中释放。在这里，我们研究了融合肽中或附近的不稳定或稳定突变如何影响病毒对阿比朵尔的敏感性。敏感性的程度成比例的融合肽的稳定性的程度上的融合前HA：稳定的突变体更敏感，和不稳定的耐阿比朵尔。代表性野生型（WT）和突变型病毒的单病毒体膜融合实验表明，耐药性是融合肽去稳定化的直接结果，不需要降低阿比朵尔与HA的结合。我们的研究结果支持的模型，其中的概率个别HA延伸到从事目标膜是由两个关键的力量的复合物：一个“拖船”的融合肽的HA重排附近的阿比朵尔结合位点和关键的相互作用稳定的融合肽在融合前口袋。阿比朵尔增加和不稳定的突变降低了融合肽释放的自由能成本，解释了观察到的耐药性。我们的研究结果具有广泛的影响融合抑制剂的设计，病毒的耐药机制，我们的HA介导的膜融合的基本理解。
Understanding mechanisms of resistance to antiviral inhibitors can reveal nuanced features of targeted viral mechanisms and, in turn, lead to improved strategies for inhibitor design. Arbidol is a broad-spectrum antiviral that binds to and prevents the fusion-associated conformational changes in the trimeric influenza A virus (IAV) hemagglutinin (HA). The rate-limiting step during the HA-mediated membrane fusion is the release of the hydrophobic fusion peptides from a conserved pocket on HA. Here, we investigated how destabilizing or stabilizing mutations in or near the fusion peptide affect viral sensitivity to Arbidol. The degree of sensitivity was proportional to the extent of fusion-peptide stability on the prefusion HA: stabilized mutants were more sensitive, and destabilized ones were resistant to Arbidol. Single-virion membrane fusion experiments for representative wild-type (WT) and mutant viruses demonstrated that resistance is a direct consequence of fusion-peptide destabilization not requiring reduced Arbidol binding to HA. Our results support the model whereby the probability of individual HAs extending to engage the target membrane is determined by the composite of two critical forces: a “tug” on the fusion peptide by HA rearrangements near the Arbidol binding site and the key interactions stabilizing the fusion peptide in the prefusion pocket. Arbidol increases and destabilizing mutations decrease the free-energy cost for fusion-peptide release, accounting for the observed resistance. Our findings have broad implications for fusion inhibitor design, viral mechanisms of resistance, and our basic understanding of HA-mediated membrane fusion.
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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作者：
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通讯作者：
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