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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...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8304516 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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