Inhibition of SARS-CoV-2 Infection by Human Defensin HNP1 and Retrocyclin RC-101.

Elena Kudryashova, Ashley Zani, Geraldine Vilmen, Amit Sharma, Wuyuan Lu, Jacob S Yount, Dmitri S Kudryashov

Journal of molecular biology 2022 Mar 30

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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. Copyright © 2021 Elsevier Ltd. All rights reserved.

Citation

Elena Kudryashova, Ashley Zani, Geraldine Vilmen, Amit Sharma, Wuyuan Lu, Jacob S Yount, Dmitri S Kudryashov. Inhibition of SARS-CoV-2 Infection by Human Defensin HNP1 and Retrocyclin RC-101. Journal of molecular biology. 2022 Mar 30;434(6):167225