The free fatty acid-binding pocket is a conserved hallmark in pathogenic ?-coronavirus spike proteins from SARS-CoV to Omicron.

As coronavirus disease 2019 (COVID-19) persists, severe acute 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 ?-coronaviruses (?-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.
Mesh Terms:
COVID-19, Fatty Acids, Nonesterified, Humans, SARS-CoV-2, Spike Glycoprotein, Coronavirus
Sci Adv
Date: Nov. 25, 2022
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