SARS‐CoV‐2 Spike Protein‐Derived Cyclic Peptides as Modulators of Spike Interaction with GRP78

Abstract

AbstractThe human glucose‐regulated protein GRP78 is a human chaperone that translocactes to the cell surface when cells are under stress. Theoretical studies suggested it could be involved in SARS‐CoV‐2 virus entry to cells. In this work, we used in vitro surface plasmon resonance‐based assays to show that human GRP78 indeed binds to SARS‐CoV‐2 spike protein. We have designed and synthesised cyclic peptides based on the loop structure of amino acids 480–488 of the SARS‐CoV‐2 spike protein S1 domain from the Wuhan and Omicron variants and showed that both peptides bind to GRP78. Consistent with the greater infectiousness of the Omicron variant, the Omicron‐derived peptide displays slower dissociation from the target protein. Both peptides significantly inhibit the binding of wild‐type S1 protein to the human protein GRP78 suggesting that further development of these cyclic peptide motifs may provide a viable route to novel anti‐SARS‐CoV‐2 agents.