Discovery of Nanosota-9 as anti-Omicron nanobody therapeutic candidate

作者：Gang Ye, Fan Bu, Divyasha Saxena, Hailey Turner‐Hubbard, Morgan Herbst, Benjamin W. Spiller, Brian E. Wadzinski, Lanying Du, Bin Liu, Jian Zheng, Fang Li · 发表于：PLoS Pathogens · 年份：2024 · DOI：10.1371/journal.ppat.1012726 · 被引用次数：8 · 研究领域：SARS-CoV-2 and COVID-19 Research、Bacteriophages and microbial interactions、Monoclonal and Polyclonal Antibodies Research

Omicron subvariants of SARS-CoV-2 continue to pose a significant global health threat. Nanobodies, single-domain antibodies derived from camelids, are promising therapeutic tools against pandemic viruses due to their favorable properties. In this study, we identified a novel nanobody, Nanosota-9, which demonstrates high potency against a wide range of Omicron subvariants both in vitro and in a mouse model. Cryo-EM data revealed that Nanosota-9 neutralizes Omicron through a unique mechanism: two Nanosota-9 molecules crosslink two receptor-binding domains (RBDs) of the trimeric Omicron spike protein, preventing the RBDs from binding to the ACE2 receptor. This mechanism explains its strong anti-Omicron potency. Additionally, the Nanosota-9 binding epitopes on the spike protein are relatively conserved among Omicron subvariants, contributing to its broad anti-Omicron spectrum. Combined with our recently developed structure-guided in vitro evolution approach for nanobodies, Nanosota-9 has the potential to serve as the foundation for a superior anti-Omicron therapeutic.