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SARS-CoV-2 Spike Protein-Derived Cyclic Peptides as Modulators of Spike Interaction with GRP78
Authors: Johnson, N.; Pattinson, C.; Burgoyne, K.; Hijazi, K.; Houssen, W.; Milne, B.F.
Ref.: ChemBioChem 25 (12) (2024)
Abstract: The 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. The chaperone protein GRP78 mediates cell entry by various pathogens, including SARS-CoV-2. Cyclic peptides based on surface features of SARS-CoV-2 spike protein were synthesised and found to inhibit spike interaction with GRP78. Wuhan and Omicron spike sequences were compared with the known GRP78 ligand Pep42, with the Omicron-derived peptide showing the highest activity. image
