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A Fungal Defensin Targets the SARS−CoV−2 Spike Receptor−Binding Domain

Coronavirus Disease 2019 (COVID−19) elicited by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS−CoV−2) is calling for novel targeted drugs. Since the viral entry into host cells depends on specific interactions between the receptor−binding domain (RBD) of the viral Spike protein and the me...

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Autores principales: Gao, Bin, Zhu, Shunyi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304516/
https://www.ncbi.nlm.nih.gov/pubmed/34356932
http://dx.doi.org/10.3390/jof7070553
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author Gao, Bin
Zhu, Shunyi
author_facet Gao, Bin
Zhu, Shunyi
author_sort Gao, Bin
collection PubMed
description Coronavirus Disease 2019 (COVID−19) elicited by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS−CoV−2) is calling for novel targeted drugs. Since the viral entry into host cells depends on specific interactions between the receptor−binding domain (RBD) of the viral Spike protein and the membrane−bound monocarboxypeptidase angiotensin converting enzyme 2 (ACE2), the development of high affinity RBD binders to compete with human ACE2 represents a promising strategy for the design of therapeutics to prevent viral entry. Here, we report the discovery of such a binder and its improvement via a combination of computational and experimental approaches. The binder micasin, a known fungal defensin from the dermatophytic fungus Microsporum canis with antibacterial activity, can dock to the crevice formed by the receptor−binding motif (RBM) of RBD via an extensive shape complementarity interface (855.9 Å2 in area) with numerous hydrophobic and hydrogen−bonding interactions. Using microscale thermophoresis (MST) technique, we confirmed that micasin and its C−terminal γ−core derivative with multiple predicted interacting residues exhibited a low micromolar affinity to RBD. Expanding the interface area of micasin through a single point mutation to 970.5 Å2 accompanying an enhanced hydrogen bond network significantly improved its binding affinity by six−fold. Our work highlights the naturally occurring fungal defensins as an emerging resource that may be suitable for the development into antiviral agents for COVID−19.
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spelling pubmed-83045162021-07-25 A Fungal Defensin Targets the SARS−CoV−2 Spike Receptor−Binding Domain Gao, Bin Zhu, Shunyi J Fungi (Basel) Article Coronavirus Disease 2019 (COVID−19) elicited by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS−CoV−2) is calling for novel targeted drugs. Since the viral entry into host cells depends on specific interactions between the receptor−binding domain (RBD) of the viral Spike protein and the membrane−bound monocarboxypeptidase angiotensin converting enzyme 2 (ACE2), the development of high affinity RBD binders to compete with human ACE2 represents a promising strategy for the design of therapeutics to prevent viral entry. Here, we report the discovery of such a binder and its improvement via a combination of computational and experimental approaches. The binder micasin, a known fungal defensin from the dermatophytic fungus Microsporum canis with antibacterial activity, can dock to the crevice formed by the receptor−binding motif (RBM) of RBD via an extensive shape complementarity interface (855.9 Å2 in area) with numerous hydrophobic and hydrogen−bonding interactions. Using microscale thermophoresis (MST) technique, we confirmed that micasin and its C−terminal γ−core derivative with multiple predicted interacting residues exhibited a low micromolar affinity to RBD. Expanding the interface area of micasin through a single point mutation to 970.5 Å2 accompanying an enhanced hydrogen bond network significantly improved its binding affinity by six−fold. Our work highlights the naturally occurring fungal defensins as an emerging resource that may be suitable for the development into antiviral agents for COVID−19. MDPI 2021-07-12 /pmc/articles/PMC8304516/ /pubmed/34356932 http://dx.doi.org/10.3390/jof7070553 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gao, Bin
Zhu, Shunyi
A Fungal Defensin Targets the SARS−CoV−2 Spike Receptor−Binding Domain
title A Fungal Defensin Targets the SARS−CoV−2 Spike Receptor−Binding Domain
title_full A Fungal Defensin Targets the SARS−CoV−2 Spike Receptor−Binding Domain
title_fullStr A Fungal Defensin Targets the SARS−CoV−2 Spike Receptor−Binding Domain
title_full_unstemmed A Fungal Defensin Targets the SARS−CoV−2 Spike Receptor−Binding Domain
title_short A Fungal Defensin Targets the SARS−CoV−2 Spike Receptor−Binding Domain
title_sort fungal defensin targets the sars−cov−2 spike receptor−binding domain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304516/
https://www.ncbi.nlm.nih.gov/pubmed/34356932
http://dx.doi.org/10.3390/jof7070553
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