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

Area of Science:

• Virology
• Molecular Biology
• Biochemistry

Background:

• The human glucose-regulated protein GRP78 is a cellular chaperone that relocates to the cell surface under stress conditions.
• Theoretical studies proposed GRP78's potential role in SARS-CoV-2 viral entry into host cells.

Purpose of the Study:

• To investigate the interaction between human GRP78 and SARS-CoV-2 spike protein.
• To design and evaluate cyclic peptides derived from SARS-CoV-2 spike protein variants for their ability to inhibit this interaction.

Main Methods:

• In vitro surface plasmon resonance (SPR) assays were employed to confirm binding between human GRP78 and SARS-CoV-2 spike protein.
• Cyclic peptides were synthesized based on the amino acid loop structure (480-488) of the S1 domain from Wuhan and Omicron SARS-CoV-2 variants.

Main Results:

• Human GRP78 was confirmed to bind to the SARS-CoV-2 spike protein.
• Both Wuhan and Omicron-derived cyclic peptides demonstrated binding to GRP78.
• The Omicron-derived peptide exhibited slower dissociation kinetics compared to the Wuhan-derived peptide.
• Both cyclic peptides significantly inhibited the binding of wild-type S1 protein to human GRP78.

Conclusions:

• Human GRP78 is a direct binding partner for the SARS-CoV-2 spike protein.
• Designed cyclic peptides targeting the GRP78-spike protein interaction show promise as therapeutic agents.
• The Omicron variant peptide's binding characteristics suggest potential for enhanced efficacy, warranting further development for novel anti-SARS-CoV-2 strategies.