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, Lok Yin Roy Wong

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number4056
JournalNature communications
Issue number1
StatePublished - Dec 2024

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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