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

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

Ruipeng Lei, Enya Qing, Abby Odle, Meng Yuan, Timothy J C Tan, Natalie So, Wenhao O Ouyang, Ian A Wilson, Tom Gallagher, Stanley Perlman, …
bioRxiv : the preprint server for biology
11/29/2023
DOI: 10.1101/2023.11.28.569051
PMCID: PMC10705381
PMID: 38076875
url
https://doi.org/10.1101/2023.11.28.569051View
Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

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 performed 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 identified mutations at residue 813 of the spike protein that reduced TMPRSS2-mediated entry with decreased virulence. In addition, we showed 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.

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