Intermediates in SARS-CoV-2 spike-mediated cell entry

Tara C. Marcink, Thomas Kicmal, Emily Armbruster, Zhening Zhang, Gillian Zipursky, Kate L. Golub, Mohab Idris, Jonathan Khao, Jennifer Drew-Bear, Gael McGill, Tom Gallagher, Matteo Porotto, Amédée Des Georges, Anne Moscona

Research output: Contribution to journalArticlepeer-review


SARS-CoV-2 cell entry is completed after viral spike (S) protein-mediated membrane fusion between viral and host cell membranes. Stable prefusion and postfusion S structures have been resolved by cryo-electron microscopy and cryo-electron tomography, but the refolding intermediates on the fusion pathway are transient and have not been examined. We used an antiviral lipopeptide entry inhibitor to arrest S protein refolding and thereby capture intermediates as S proteins interact with hACE2 and fusion-activating proteases on cell-derived target membranes. Cryo-electron tomography imaged both extended and partially folded intermediate states of S2, as well as a novel late-stage conformation on the pathway to membrane fusion. The intermediates now identified in this dynamic S protein-directed fusion provide mechanistic insights that may guide the design of CoV entry inhibitors.

Original languageEnglish (US)
Article numbereabo3153
JournalScience Advances
Issue number33
StatePublished - Aug 2022

ASJC Scopus subject areas

  • General


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