Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state.
Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state.
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DOI：
10.1038/ncomms14158
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发表时间：
2017-02-13
影响因子：
16.6
通讯作者：
Saelens X
中科院分区：
文献类型：
--
作者：
Rossey I;Gilman MS;Kabeche SC;Sedeyn K;Wrapp D;Kanekiyo M;Chen M;Mas V;Spitaels J;Melero JA;Graham BS;Schepens B;McLellan JS;Saelens X
人呼吸道合胞病毒（RSV）是引起幼儿下呼吸道感染的主要病原。RSV融合蛋白（F）是高度保守的，是唯一的病毒膜蛋白是必不可少的感染。RSV F的融合前构象被认为是抗病毒策略的最相关靶标，因为它是蛋白质的融合活性形式和人血清中存在的中和活性的主要靶标。在这里，我们描述了两个美洲驼衍生的单域抗体（VHH），具有有效的RSV中和活性，并选择性地结合融合前RSV F与皮摩尔亲和力。这些VHH与预融合F复合的晶体结构表明，它们识别由两个F原聚体形成的保守腔。此外，VHH防止RSV复制和RSV攻击小鼠中炎性单核细胞和T细胞的肺浸润。这些融合前F-特异性VHH代表有希望的抗RSV的抗病毒剂。呼吸道合胞病毒（RSV）的中和抗体可以减少住院儿童的疾病，但目前的选择显示疗效有限。在这里，作者从美洲驼中分离出有效的单域抗体，该抗体识别RSV F的融合前构象并防止RSV在小鼠中复制。
Human respiratory syncytial virus (RSV) is the main cause of lower respiratory tract infections in young children. The RSV fusion protein (F) is highly conserved and is the only viral membrane protein that is essential for infection. The prefusion conformation of RSV F is considered the most relevant target for antiviral strategies because it is the fusion-competent form of the protein and the primary target of neutralizing activity present in human serum. Here, we describe two llama-derived single-domain antibodies (VHHs) that have potent RSV-neutralizing activity and bind selectively to prefusion RSV F with picomolar affinity. Crystal structures of these VHHs in complex with prefusion F show that they recognize a conserved cavity formed by two F protomers. In addition, the VHHs prevent RSV replication and lung infiltration of inflammatory monocytes and T cells in RSV-challenged mice. These prefusion F-specific VHHs represent promising antiviral agents against RSV. Neutralizing antibodies for respiratory syncytial virus (RSV) can reduce disease in hospitalized children, but current options show limited efficacy. Here, the authors isolate potent single-domain antibodies from llamas that recognize the prefusion conformation of RSV F and prevent RSV replication in mice.