Dose-Dependent Influence of RBD-Derived Amyloidogenic Peptides on SARS-CoV-2 Infectivity: A Cautionary Tale for...

Area of Science:

• Virology
• Biochemistry
• Drug Development

Background:

• The receptor-binding domain (RBD) of SARS-CoV-2 Spike protein is a key target for antiviral therapies.
• Omicron variant's RBD shows increased amyloidogenic regions, suggesting potential roles for peptide fragments.
• Amyloidogenic peptides may influence Spike protein function and host-virus interactions.

Purpose of the Study:

• To characterize two short RBD-derived peptides (Pep-2 and Pep-3) from ancestral and Omicron variants.
• To investigate their potential for amyloid formation and interaction with Spike RBD and ACE2 receptor.
• To evaluate their dose-dependent effects on viral infection and host cells.

Main Methods:

• Cell-based assays (cytotoxicity, infection models) using human lung fibroblasts, A549, and Vero E6 cells.
• Fluorescence spectroscopy (Thioflavin-T assay) to detect amyloid fibril formation.
• Multiscale computational modeling to analyze peptide-RBD and peptide-ACE2 interactions.

Main Results:

• Peptides showed no intrinsic cytotoxicity in lung cells but were toxic to Vero E6 cells.
• Peptides exhibited a dose-dependent effect on viral infection, enhancing cytopathic effects at low concentrations and inhibiting infection at high concentrations.
• No stable amyloid fibrils were detected; computational analysis revealed heterogeneous binding modes to Spike RBD and comparable ACE2 binding affinities.

Conclusions:

• Short amyloidogenic RBD peptides have a complex, dose-dependent antiviral profile.
• Interactions with both viral and host factors (including ACE2) modulate infection outcomes.
• Targeted peptide design leveraging amyloidogenic features shows promise for antiviral therapy.