Functional and antigenic characterization of SARS-CoV-2 spike fusion peptide by deep mutational scanning

Author:

Lei RuipengORCID,Qing EnyaORCID,Odle Abby,Yuan MengORCID,Gunawardene Chaminda D.,Tan Timothy J. C.ORCID,So Natalie,Ouyang Wenhao O.,Wilson Ian A.ORCID,Gallagher TomORCID,Perlman StanleyORCID,Wu Nicholas C.ORCID,Wong Lok-Yin RoyORCID

Abstract

AbstractThe fusion peptide of SARS-CoV-2 spike protein is functionally important for membrane fusion during virus entry and is part of a broadly neutralizing epitope. However, sequence determinants at the fusion peptide and its adjacent regions for pathogenicity and antigenicity remain elusive. In this study, we perform a series of deep mutational scanning (DMS) experiments on an S2 region spanning the fusion peptide of authentic SARS-CoV-2 in different cell lines and in the presence of broadly neutralizing antibodies. We identify mutations at residue 813 of the spike protein that reduced TMPRSS2-mediated entry with decreased virulence. In addition, we show that an F823Y mutation, present in bat betacoronavirus HKU9 spike protein, confers resistance to broadly neutralizing antibodies. Our findings provide mechanistic insights into SARS-CoV-2 pathogenicity and also highlight a potential challenge in developing broadly protective S2-based coronavirus vaccines.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases

Bill and Melinda Gates Foundation

Publisher

Springer Science and Business Media LLC

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1. The biophysical landscape of viral evolution;Proceedings of the National Academy of Sciences;2024-06-24

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