Cryo-EM reveals binding of linoleic acid to SARS-CoV-2 spike glycoprotein, suggesting an antiviral treatment strategy

The COVID-19 pandemic and concomitant lockdowns presented a global health
challenge and triggered unprecedented research efforts to elucidate the
molecular mechanisms and pathogenicity of SARS-CoV-2. The spike glycoprotein decorating the surface of SARS-CoV-2 virions is a prime target for vaccine development, antibody therapy and serology as it binds the host cell receptor
and is central for viral cell entry. The electron cryo-microscopy structure of the
spike protein revealed a hydrophobic pocket in the receptor-binding domain
that is occupied by an essential fatty acid, linoleic acid (LA). The LA-bound
spike protein adopts a non-infectious locked conformation which is more stable
than the infectious form and shields important immunogenic epitopes. Here, the
impact of LA binding on viral infectivity and replication, and the evolutionary
conservation of the pocket in other highly pathogenic coronaviruses, including
SARS-CoV-2 variants of concern (VOCs), are reviewed. The importance of LA
metabolic products, the eicosanoids, in regulating the human immune response
and inflammation is highlighted. Lipid and fatty-acid binding to a hydrophobic
pocket in proteins on the virion surface appears to be a broader strategy
employed by viruses, including picornaviruses and Zika virus. Ligand binding
stabilizes their protein structure and assembly, and downregulates infectivity. In
the case of rhinoviruses, this has been exploited to develop small-molecule
antiviral drugs that bind to the hydrophobic pocket. The results suggest a
COVID-19 antiviral treatment based on the LA-binding pocket.