TY - JOUR
T1 - The Free Fatty Acid-Binding Pocket is a Conserved Hallmark in Pathogenic β-Coronavirus Spike Proteins from SARS-CoV to Omicron
AU - Toelzer, Christine
AU - Gupta, Kapil
AU - Yadav Kadapalakere, Sathish
AU - Hodgson, Lorna R
AU - Kavanagh Williamson, Maia
AU - Buzas, Dora
AU - Borucu, Ufuk
AU - Powers, Kyle T
AU - Stenner, Richard A
AU - Vasileiou, Kate
AU - Garzoni, Frederic
AU - Fitzgerald, Daniel J
AU - Payré, Christine
AU - Gautam, Gunjan
AU - Lambeau, Gérard
AU - Davidson, Andrew D
AU - Verkade, Paul
AU - Martin, Frank
AU - Berger, Imre
AU - Berger-Schaffitzel, Christiane H
PY - 2022/11/25
Y1 - 2022/11/25
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 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.
AB - 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.
U2 - 10.1101/2022.04.22.489083
DO - 10.1101/2022.04.22.489083
M3 - Article (Academic Journal)
C2 - 36417532
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 47
M1 - eadc9179
ER -