Shuo Du, Yunlong Cao, Q. Zhu, Pin Yu, F. Qi, Guopeng Wang, Xiaoxia Du, L. Bao, W. Deng, Hua Zhu, Jiangning Liu, J. Nie, Yinghui Zheng, Haoyu Liang, Ruixue Liu, Shuran Gong, Hua Xu, A. Yisimayi, Qi Lv, Bo Wang, Runsheng He, Yunlin Han, Wenjie Zhao, Yali Bai, Yajin Qu, Xiang Gao, Chenggong Ji, Qisheng Wang, Ning Gao, Weijin Huang, Youchun Wang, X. Xie, X. Su, Junyu Xiao, C. Qin
Cell, 2020
Understanding how potent neutralizing antibodies (NAbs) inhibit SARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanism is largely unknown. Here we report the 3.5-Å cryo-EM structure of BD-368-2/trimeric-spike complex, revealing that BD-368-2 fully blocks ACE2 recognition by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their “up” or “down” conformations. Also, BD-368-2 treats infected adult hamsters at low dosages and at various administering windows, in contrast to placebo hamsters that manifested severe interstitial pneumonia. Moreover, BD-368-2’s epitope completely avoids the common binding site of VH3-53/VH3-66 recurrent NAbs, evidenced by tripartite co-crystal structures with RBD. Pairing BD-368-2 with a potent recurrent NAb neutralizes SARS-CoV-2 pseudovirus at pM level and rescues mutation-induced neutralization escapes. Together, our results rationalized a new RBD epitope that leads to high neutralization potency and demonstrated BD-368-2’s therapeutic potential in treating COVID-19.
Cited by 78 publications.
Field of study: Medicine