武汉大学严欢、中国科学院武汉病毒研究所石正丽和美国华盛顿大学David Veesler研究组合作取得一项新成果。他们实现了冠状病毒受体的定制设计。这一研究成果发表在2024年10月30日出版的国际学术期刊《自然》上。

据悉，尽管冠状病毒使用多种受体，但由于缺乏感染模型，对未知受体冠状病毒的特征描述一直受到阻碍。

研究人员介绍了一种设计功能性定制病毒受体（CVR）的策略。模块化设计依赖于构建由各种模块组成的人工受体支架，并生成特定的病毒结合域。研究人员确定了CVR的关键因素，通过促进各种冠状病毒的尖峰蛋白水解、膜融合、伪病毒进入和传播，使其在功能上模拟原生受体。研究利用定制化CVR确定了功能性SARS-CoV-2穗状病毒受体的结合位点，并揭示了N端结构域通过靶向S2L20-CVR促进侵入细胞的机制。

研究人员设计了6个亚属12种代表性冠状病毒（其中大多数缺乏已知受体）的CVR表达细胞，结果表明泛沙巴病毒CVR有利于繁殖能力强的HKU3假病毒和RsHuB2019A真病毒的增殖。

利用HKU5特异性CVR，研究人员成功地挽救了野生型和ZsGreen-HiBiT感染的HKU5-1 (LMH03f)，并从蝙蝠样本中分离出了HKU5病毒株。该研究证明了CVR策略在建立独立于自身受体感染模型方面的潜力，为研究缺乏已知易感靶细胞的病毒提供了一种工具。

附：英文英文

Title: Design of customized coronavirus receptors

Author: Liu, Peng, Huang, Mei-Ling, Guo, Hua, McCallum, Matthew, Si, Jun-Yu, Chen, Yuan-Mei, Wang, Chun-Li, Yu, Xiao, Shi, Lu-Lu, Xiong, Qing, Ma, Cheng-Bao, Bowen, John E., Tong, Fei, Liu, Chen, Sun, Ye-hui, Yang, Xiao, Chen, Jing, Guo, Ming, Li, Jing, Corti, Davide, Veesler, David, Shi, Zheng-Li, Yan, Huan

Issue&Volume: 2024-10-30

Abstract: Although coronaviruses use diverse receptors, the characterization of coronaviruses with unknown receptors has been impeded by a lack of infection models1,2. Here we introduce a strategy to engineer functional customized viral receptors (CVRs). The modular design relies on building artificial receptor scaffolds comprising various modules and generating specific virus-binding domains. We identify key factors for CVRs to functionally mimic native receptors by facilitating spike proteolytic cleavage, membrane fusion, pseudovirus entry and propagation for various coronaviruses. We delineate functional SARS-CoV-2 spike receptor-binding sites for CVR design and reveal the mechanism of cell entry promoted by the N-terminal domain-targeting S2L20-CVR. We generated CVR-expressing cells for 12 representative coronaviruses from 6 subgenera, most of which lack known receptors, and show that a pan-sarbecovirus CVR supports propagation of a propagation-competent HKU3 pseudovirus and of authentic RsHuB2019A3. Using an HKU5-specific CVR, we successfully rescued wild-type and ZsGreen-HiBiT-incorporated HKU5-1 (LMH03f) and isolated a HKU5 strain from bat samples. Our study demonstrates the potential of the CVR strategy for establishing native receptor-independent infection models, providing a tool for studying viruses that lack known susceptible target cells.

DOI: 10.1038/s41586-024-08121-5

Source: https://www.nature.com/articles/s41586-024-08121-5