TY - JOUR T1 - The Free Fatty Acid-Binding Pocket is a Conserved Hallmark in Pathogenic β-Coronavirus Spike Proteins from SARS-CoV to Omicron JF - bioRxiv DO - 10.1101/2022.04.22.489083 SP - 2022.04.22.489083 AU - Christine Toelzer AU - Kapil Gupta AU - Sathish K.N. Yadav AU - Lorna Hodgson AU - Maia Kavanagh Williamson AU - Dora Buzas AU - Ufuk Borucu AU - Kyle Powers AU - Richard Stenner AU - Kate Vasileiou AU - Frederic Garzoni AU - Daniel Fitzgerald AU - Christine Payré AU - Gérard Lambeau AU - Andrew D. Davidson AU - Paul Verkade AU - Martin Frank AU - Imre Berger AU - Christiane Schaffitzel Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/04/22/2022.04.22.489083.abstract N2 - As COVID-19 persists, severe acquired respiratory syndrome coronavirus-2 (SARS-CoV-2) Variants of Concern (VOCs) emerge, accumulating spike (S) glycoprotein mutations. S receptor-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 LA-free. 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 β-CoV infection and replication, highlighting potential antiviral strategies.One-Sentence Summary Free fatty acid-binding is conserved in pathogenic β-coronavirus S proteins and suppresses viral infection and replication.Competing Interest StatementThe authors declare competing interests. I.B. and F.G. are shareholders of Imophoron Ltd, unrelated to this correspondence. D.F. and I.B. are shareholders of Geneva Biotech SARL, unrelated to this correspondence. I.B., C.S. and D.F. report shareholding in Halo Therapeutics Ltd related to this Correspondence. Patents and patent applications have been filed related to FFA therapeutic interventions. The other authors do not declare competing interests. ER -