The Free Fatty Acid-Binding Pocket is a Conserved Hallmark in Pathogenic β-Coronavirus Spike Proteins from SARS-CoV to Omicron

Christine Toelzer, Kapil Gupta, Sathish Yadav Kadapalakere, Lorna R Hodgson, Maia Kavanagh Williamson, Dora Buzas, Ufuk Borucu, Kyle T Powers, Richard A Stenner, Kate Vasileiou, Frederic Garzoni, Daniel J Fitzgerald, Christine Payré, Gunjan Gautam, Gérard Lambeau, Andrew D Davidson, Paul Verkade, Frank Martin*, Imre Berger*, Christiane H Berger-Schaffitzel*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

14 Citations (Scopus)
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Abstract

As COVID-19 persists, severe acquired respiratory syndrome coronavirus-2 (SARS-CoV-2) Variants of Concern (VOCs) emerge, accumulating spike (S) glycoprotein mutations. S receptor37 binding domain (RBD) comprises a free fatty acid (FFA)-binding pocket. FFA-binding stabilizes a locked S conformation, interfering with virus infectivity. We provide evidence that the pocket is conserved in pathogenic β-coronaviruses (β-CoVs) infecting humans. SARS-CoV, MERS-CoV, SARS-CoV-2 and VOCs bind the essential FFA linoleic acid (LA), while binding is abolished by one mutation in common cold-causing HCoV-HKU1. In the SARS-CoV S structure, LA stabilizes the locked conformation while the open, infectious conformation is devoid of LA. Electron tomography of SARS-CoV-2 infected cells reveals that LA treatment inhibits viral replication, resulting in fewer, deformed virions. Our results establish FFA-binding as a hallmark of pathogenic -CoV infection and replication, setting the stage for FFA-based antiviral strategies to overcome COVID-19.
Original languageEnglish
Article numbereadc9179
Number of pages12
JournalScience Advances
Volume8
Issue number47
Early online date23 Nov 2022
DOIs
Publication statusPublished - 25 Nov 2022

Structured keywords

  • Bristol BioDesign Institute
  • Max Planck Bristol

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