Human Defensin Peptides Can Block SARS-CoV-2 Infection by Destabilizing the Spike Protein

The researchers used multiple in vitro assays: binding affinity measurements between defensins and Spike protein, Spike-mediated membrane fusion assays, Spike-pseudotyped lentivirus infection assays, and authentic SARS-CoV-2 infection experiments in cell culture. They tested the effects with and without serum to assess physiological relevance. Protein destabilization and precipitation assays characterized the mechanism of Spike inactivation.

Understanding how the body's own antimicrobial peptides fight SARS-CoV-2 illuminates natural defense mechanisms that work regardless of viral variants. Unlike vaccines and antibodies that target specific Spike protein sequences, defensins work by physically destabilizing the protein structure — a mechanism that could remain effective against future variants. This knowledge could inform the development of defensin-based antiviral therapies or nasal sprays for infection prevention.

Defensins represent an ancient arm of immunity that predates adaptive immune responses. This study adds SARS-CoV-2 to the growing list of viruses that defensins can neutralize through protein destabilization. As concerns about emerging variants and pandemic preparedness persist, variant-agnostic antiviral approaches based on innate immune peptides could complement vaccines and monoclonal antibodies, which can be rendered less effective by mutations in the Spike protein.

All experiments were conducted in cell culture — in vivo antiviral efficacy in animals or humans has not been tested. Serum significantly reduced HNP1 activity, raising questions about whether physiological concentrations in the respiratory tract are sufficient for meaningful antiviral effects. The study does not address defensin stability in the airways or potential toxicity at the high concentrations needed to overcome serum inhibition. Only two defensins were tested against one virus strain.