Structural insights into the rational design of a nanobody that binds with high affinity to the SARS-CoV-2 spike variant
Structural insights into the rational design of a nanobody that binds with high affinity to the SARS-CoV-2 spike variant
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对与 SARS-CoV-2 尖峰变体高亲和力结合的纳米抗体合理设计的结构见解
DOI：
10.1093/jb/mvac096
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Inoue Tsuyoshi
中科院分区：
文献类型：
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作者：
Yamaguchi Keishi;Anzai Itsuki;Maeda Ryota;Moriguchi Maiko;Watanabe Tokiko;Imura Akihiro;Takaori-Kondo Akifumi;Inoue Tsuyoshi
与病毒适应性进化相关的严重急性呼吸综合征冠状病毒2型变异体的不断出现正在延长2019年全球冠状病毒病(新冠肺炎)大流行的时间。基于结构信息的中和抗体的修饰有望成为快速对抗新出现的变种的有用方法。重链抗体(VHH)P17重链可变区的二聚化已被报道，它对SARS-CoV-2具有很强的中和活性，但与该表位的相互作用方式尚不清楚。在这里，我们报道了与SARS-CoV-2受体结合域(RBD)结合的单体P17的X射线晶体结构，并用动力学方法研究了P17与各种关注变异体(VOCs)的结合活性。结构揭示了结合界面的细节，并表明P17具有合适的连接子长度，以产生亲和力效应并识别广泛的RBD取向。此外，我们在已知的VOC中发现了降低P17结合亲和力的突变，并提出了获得与Omicron RBD亲和力的方法，因为Omicron是目前最主要的VOC。本研究为合理设计针对新兴VOCs的有效VHH提供了参考。
The continuous emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants associated with the adaptive evolution of the virus is prolonging the global coronavirus disease 2019 (COVID-19) pandemic. The modification of neutralizing antibodies based on structural information is expected to be a useful approach to rapidly combat emerging variants. A dimerized variable domain of heavy chain of heavy chain antibody (VHH) P17 that has highly potent neutralizing activity against SARS-CoV-2 has been reported but the mode of interaction with the epitope remains unclear. Here, we report the X-ray crystal structure of the complex of monomerized P17 bound to the SARS-CoV-2 receptor binding domain (RBD) and investigated the binding activity of P17 toward various variants of concern (VOCs) using kinetics measurements. The structure revealed details of the binding interface and showed that P17 had an appropriate linker length to have an avidity effect and recognize a wide range of RBD orientations. Furthermore, we identified mutations in known VOCs that decrease the binding affinity of P17 and proposed methods for the acquisition of affinity toward the Omicron RBD because Omicron is currently the most predominant VOC. This study provides information for the rational design of effective VHHs for emerging VOCs.