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

• Published in: Chembiochem : a European journal of chemical biology Vol. 25; no. 12; pp. e202300789 - n/a
• Main Authors: Johnson, Nicholas, Pattinson, Craig, Burgoyne, Kate, Hijazi, Karolin, Houssen, Wael E., Milne, Bruce F.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 17.06.2024; John Wiley and Sons Inc
• Subjects: Amino acids; BiP; Cell surface; COVID-19; COVID-19 - metabolism; COVID-19 - virology; Cyclic peptides; Endoplasmic Reticulum Chaperone BiP; GRP78; Heat-Shock Proteins - chemistry; Heat-Shock Proteins - metabolism; HSPA5; Humans; Modulators; Peptides; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; Peptides, Cyclic - pharmacology; Protein Binding; Proteins; SARS-CoV-2; SARS-CoV-2 - drug effects; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; Surface plasmon resonance; BiP; GRP78; SARS-CoV-2; HSPA5; Cyclic peptides
• ISSN: 1439-4227; 1439-7633; 1439-7633
• DOI: 10.1002/cbic.202300789

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.