Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is an enveloped virus responsible for the
COVID-19 pandemic. The emergence of new potentially more transmissible and
vaccine-resistant variants of SARS-CoV-2 is an ever-present threat. Thus, it remains essential to better understand innate immune mechanisms that can inhibit the virus. One component of the innate immune system with broad antipathogen, including
antiviral, activity is a group of cationic immune
peptides termed
defensins. The ability of
defensins to neutralize enveloped and non-enveloped viruses and to inactivate numerous
bacterial toxins correlate with their ability to promote the unfolding of
proteins with high conformational plasticity. We found that human neutrophil α-
defensin HNP1 binds to
SARS-CoV-2 Spike protein with submicromolar affinity that is more than 20 fold stronger than its binding to
serum albumin. As such, HNP1, as well as a θ-
defensin retrocyclin RC-101, both interfere with Spike-mediated membrane fusion, Spike-pseudotyped
lentivirus infection, and authentic
SARS-CoV-2 infection in cell culture. These effects correlate with the abilities of the
defensins to destabilize and precipitate Spike
protein and inhibit the interaction of Spike with the ACE2 receptor. Serum reduces the anti-SARS-CoV-2 activity of HNP1, though at high concentrations, HNP1 was able to inactivate the virus even in the presence of serum. Overall, our results suggest that
defensins can negatively affect the native conformation of SARS-CoV-2 Spike, and that α- and θ-
defensins may be valuable tools in developing
SARS-CoV-2 infection prevention strategies.