School of Biochemistry, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
Science. 2020 Nov 13;370(6518):861-865. doi: 10.1126/science.abd3072. Epub 2020 Oct 20.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), uses the viral spike (S) protein for host cell attachment and entry. The host protease furin cleaves the full-length precursor S glycoprotein into two associated polypeptides: S1 and S2. Cleavage of S generates a polybasic Arg-Arg-Ala-Arg carboxyl-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that binds to cell surface neuropilin-1 (NRP1) and NRP2 receptors. We used x-ray crystallography and biochemical approaches to show that the S1 CendR motif directly bound NRP1. Blocking this interaction by RNA interference or selective inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture. NRP1 thus serves as a host factor for SARS-CoV-2 infection and may potentially provide a therapeutic target for COVID-19.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）是导致 2019 年冠状病毒病（COVID-19）的病原体，它利用病毒刺突（S）蛋白附着和进入宿主细胞。宿主蛋白酶弗林（furin）将全长前体 S 糖蛋白切割成两个相关的多肽：S1 和 S2。S 的切割在 S1 上产生一个多碱性的精氨酸-精氨酸-丙氨酸-精氨酸羧基末端序列，该序列符合 C 端规则（CendR）基序，与细胞表面神经纤毛蛋白-1（NRP1）和 NRP2 受体结合。我们使用 X 射线晶体学和生化方法表明，S1 CendR 基序直接与 NRP1 结合。通过 RNA 干扰或选择性抑制剂阻断这种相互作用，可降低 SARS-CoV-2 在细胞培养中的进入和感染性。因此，NRP1 是 SARS-CoV-2 感染的宿主因子，可能为 COVID-19 提供治疗靶点。
