Vitamin D-inducible antimicrobial peptide LL-37 binds SARS-CoV-2 Spike and accessory proteins ORF7a and ORF8
Annika Roth, Steffen Lütke, Matthias Mörgelin, Denise Meinberger, Gabriele Hermes, Gerhard Sengle, Manuel Koch, Marco Drexelius, Jan Gebauer, Ines Neundorf, Dzemal Elezagic, Mats Paulsson, Thomas Streichert, Andreas R Klatt
Frontiers in Cellular and Infection Microbiology, doi:10.3389/fcimb.2025.1671738
Background: The role of vitamin D in Coronavirus Disease 2019 outcomes remains debated, but emerging evidence suggests it may enhance recovery by strengthening immune responses. Vitamin D upregulates LL-37, an antimicrobial peptide with broad antiviral activity, including potential benefits against SARS-CoV-2. LL-37's interactions with viral proteins, however, remain incompletely understood. Methods: We investigated LL-37's interactions with the SARS-CoV-2 Spike glycoprotein and the accessory proteins ORF7a and ORF8 using surface plasmon resonance and negative-stain electron microscopy. These approaches were employed to assess LL-37's binding capabilities and potential impact on viral infectivity. Results: LL-37 bound multiple domains of the Spike protein and inhibited its interaction with the human angiotensin-converting enzyme 2 (hACE2) receptor in vitro. Up to seven LL-37 molecules were observed surrounding Spike, forming a halo-like structure that may block receptor engagement. LL-37 also bound to ORF7a and ORF8, potentially impairing their ability to disrupt host cell processes. Notably, LL-37's interaction with ORF7a may prevent degradation of SNAP29, restoring autophagy and promoting viral clearance.
Funding The author(s) declare financial support was received for the research and/or publication of this article. Funding for this study was provided by the Deutsche Forschungsgemeinschaft (DFG) via 384170921 FOR2722/ C2 to GS, FOR2722/B2 to MK, and FOR2722/B1 to MP.
Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement The author(s) declare that Generative AI was used in the creation of this manuscript. During the preparation of this work the authors used Chat GPT in order to assist with improving the clarity, structure, and grammar of the manuscript text. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
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"abstract": "<jats:sec><jats:title>Background</jats:title><jats:p>The role of vitamin D in Coronavirus Disease 2019 (COVID-19) outcomes remains debated, but emerging evidence suggests it may enhance recovery by strengthening immune responses. Vitamin D upregulates LL-37, an antimicrobial peptide with broad antiviral activity, including potential benefits against SARS-CoV-2. LL-37’s interactions with viral proteins, however, remain incompletely understood.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We investigated LL-37’s interactions with the SARS-CoV-2 Spike glycoprotein and the accessory proteins ORF7a and ORF8 using surface plasmon resonance and negative-stain electron microscopy. These approaches were employed to assess LL-37’s binding capabilities and potential impact on viral infectivity.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>LL-37 bound multiple domains of the Spike protein and inhibited its interaction with the human angiotensin-converting enzyme 2 (hACE2) receptor <jats:italic>in vitro</jats:italic>. Up to seven LL-37 molecules were observed surrounding Spike, forming a halo-like structure that may block receptor engagement. LL-37 also bound to ORF7a and ORF8, potentially impairing their ability to disrupt host cell processes. Notably, LL-37’s interaction with ORF7a may prevent degradation of SNAP29, restoring autophagy and promoting viral clearance.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>LL-37 disrupts key viral-host interactions by binding to Spike, ORF7a, and ORF8, thereby reducing SARS-CoV-2 infectivity. These findings highlight LL-37’s potential as a therapeutic agent in COVID-19 and provide mechanistic insight into its antiviral actions.</jats:p></jats:sec>",
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