Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant

Yang Liu, Jianying Liu, Bryan A. Johnson, Hongjie Xia, Zhiqiang Ku, Craig Schindewolf, Steven G. Widen, Zhiqiang An, Scott C. Weaver, Vineet D. Menachery, Xuping Xie, Pei Yong Shi

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


We report that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta spike mutation P681R plays a key role in the Alpha-to-Delta variant replacement during the coronavirus disease 2019 (COVID-19) pandemic. Delta SARS-CoV-2 efficiently outcompetes the Alpha variant in human lung epithelial cells and primary human airway tissues. The Delta spike mutation P681R is located at a furin cleavage site that separates the spike 1 (S1) and S2 subunits. Reverting the P681R mutation to wild-type P681 significantly reduces the replication of the Delta variant to a level lower than the Alpha variant. Mechanistically, the Delta P681R mutation enhances the cleavage of the full-length spike to S1 and S2, which could improve cell-surface-mediated virus entry. In contrast, the Alpha spike also has a mutation at the same amino acid (P681H), but the cleavage of the Alpha spike is reduced compared with the Delta spike. Our results suggest P681R as a key mutation in enhancing Delta-variant replication via increased S1/S2 cleavage.

Original languageEnglish (US)
Article number110829
JournalCell Reports
Issue number7
StatePublished - May 17 2022


  • CP: Microbiology
  • Delta variant
  • S1/S2 cleavage
  • SARS-CoV-2
  • fitness
  • human airway culture
  • spike P681R
  • viral entry

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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