A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability

Chi, X.; Yan, R.; Zhang, J.; Zhang, G.; Zhang, Y.; Hao, M.; Zhang, Z.; Fan, P.; Dong, Y.; Yang, Y.; Chen, Z.; Guo, Y.; Li, Y.; Song, X.; Chen, Y.; Xia, L.; Fu, L.; Hou, L.; Xu, J.; Yu, C.; Li, J.; Zhou, Q.; Chen, W.

doi:10.1101/2020.05.08.083964

bioRxiv · 10.1101/2020.05.08.083964

A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability

Chi, X.·Yan, R.·Zhang, J.·Zhang, G.·Zhang, Y.·Hao, M.·Zhang, Z.·Fan, P.·Dong, Y.·Yang, Y.·Chen, Z.·Guo, Y.·Li, Y.·Song, X.·Chen, Y.·Xia, L.·Fu, L.·Hou, L.·Xu, J.·Yu, C.·Li, J.·Zhou, Q.·Chen, W.

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Abstract

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global public health threat. Most research on therapeutics against SARS-CoV-2 focused on the receptor binding domain (RBD) of the Spike (S) protein, whereas the vulnerable epitopes and functional mechanism of non-RBD regions are poorly understood. Here we isolated and characterized monoclonal antibodies (mAbs) derived from convalescent COVID-19 patients. An mAb targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, although it does not block the interaction between angiotensin-converting enzyme 2 (ACE2) receptor and S protein. The cryo-EM structure of the SARS-CoV-2 S protein in complex with 4A8 has been determined to an overall resolution of 3.1 Angstrom and local resolution of 3.4 Angstrom for the 4A8-NTD interface, revealing detailed interactions between the NTD and 4A8. Our functional and structural characterizations discover a new vulnerable epitope of the S protein and identify promising neutralizing mAbs as potential clinical therapy for COVID-19.

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Chi, X., Yan, R., Zhang, J., Zhang, G., Zhang, Y., Hao, M., Zhang, Z., Fan, P., Dong, Y., Yang, Y., Chen, Z., Guo, Y., Li, Y., Song, X., Chen, Y., Xia, L., Fu, L., Hou, L., Xu, J., Yu, C., Li, J., Zhou, Q., Chen, W.. 2020-05-08. A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability. https://doi.org/10.1101/2020.05.08.083964

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