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

Ruipeng Lei, Enya Qing, Abby Odle, Meng Yuan, Chaminda D. Gunawardene, Timothy J. C. Tan, Natalie So, Wenhao O. Ouyang, Ian A. Wilson, Tom Gallagher (), Stanley Perlman (), Nicholas C. Wu () and Lok-Yin Roy Wong ()
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Ruipeng Lei: University of Illinois at Urbana-Champaign
Enya Qing: Loyola University Chicago
Abby Odle: University of Iowa
Meng Yuan: The Scripps Research Institute
Chaminda D. Gunawardene: Rutgers New Jersey Medical School
Timothy J. C. Tan: University of Illinois at Urbana-Champaign
Natalie So: University of Illinois at Urbana-Champaign
Wenhao O. Ouyang: University of Illinois at Urbana-Champaign
Ian A. Wilson: The Scripps Research Institute
Tom Gallagher: Loyola University Chicago
Stanley Perlman: University of Iowa
Nicholas C. Wu: University of Illinois at Urbana-Champaign
Lok-Yin Roy Wong: University of Iowa

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract The 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.

Date: 2024
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DOI: 10.1038/s41467-024-48104-8

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