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Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming

Processing of certain viral proteins and bacterial toxins by host serine proteases is a frequent and critical step in virulence. The coronavirus spike glycoprotein contains three (S1, S2, and S2′) cleavage sites that are processed by human host proteases. The exact nature of these cleavage sites, an...

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Autores principales: Barile, Elisa, Baggio, Carlo, Gambini, Luca, Shiryaev, Sergey A., Strongin, Alex Y., Pellecchia, Maurizio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287953/
https://www.ncbi.nlm.nih.gov/pubmed/32455942
http://dx.doi.org/10.3390/molecules25102424
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author Barile, Elisa
Baggio, Carlo
Gambini, Luca
Shiryaev, Sergey A.
Strongin, Alex Y.
Pellecchia, Maurizio
author_facet Barile, Elisa
Baggio, Carlo
Gambini, Luca
Shiryaev, Sergey A.
Strongin, Alex Y.
Pellecchia, Maurizio
author_sort Barile, Elisa
collection PubMed
description Processing of certain viral proteins and bacterial toxins by host serine proteases is a frequent and critical step in virulence. The coronavirus spike glycoprotein contains three (S1, S2, and S2′) cleavage sites that are processed by human host proteases. The exact nature of these cleavage sites, and their respective processing proteases, can determine whether the virus can cross species and the level of pathogenicity. Recent comparisons of the genomes of the highly pathogenic SARS-CoV2 and MERS-CoV, with less pathogenic strains (e.g., Bat-RaTG13, the bat homologue of SARS-CoV2) identified possible mutations in the receptor binding domain and in the S1 and S2′ cleavage sites of their spike glycoprotein. However, there remains some confusion on the relative roles of the possible serine proteases involved for priming. Using anthrax toxin as a model system, we show that in vivo inhibition of priming by pan-active serine protease inhibitors can be effective at suppressing toxicity. Hence, our studies should encourage further efforts in developing either pan-serine protease inhibitors or inhibitor cocktails to target SARS-CoV2 and potentially ward off future pandemics that could develop because of additional mutations in the S-protein priming sequence in coronaviruses.
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spelling pubmed-72879532020-06-15 Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming Barile, Elisa Baggio, Carlo Gambini, Luca Shiryaev, Sergey A. Strongin, Alex Y. Pellecchia, Maurizio Molecules Article Processing of certain viral proteins and bacterial toxins by host serine proteases is a frequent and critical step in virulence. The coronavirus spike glycoprotein contains three (S1, S2, and S2′) cleavage sites that are processed by human host proteases. The exact nature of these cleavage sites, and their respective processing proteases, can determine whether the virus can cross species and the level of pathogenicity. Recent comparisons of the genomes of the highly pathogenic SARS-CoV2 and MERS-CoV, with less pathogenic strains (e.g., Bat-RaTG13, the bat homologue of SARS-CoV2) identified possible mutations in the receptor binding domain and in the S1 and S2′ cleavage sites of their spike glycoprotein. However, there remains some confusion on the relative roles of the possible serine proteases involved for priming. Using anthrax toxin as a model system, we show that in vivo inhibition of priming by pan-active serine protease inhibitors can be effective at suppressing toxicity. Hence, our studies should encourage further efforts in developing either pan-serine protease inhibitors or inhibitor cocktails to target SARS-CoV2 and potentially ward off future pandemics that could develop because of additional mutations in the S-protein priming sequence in coronaviruses. MDPI 2020-05-22 /pmc/articles/PMC7287953/ /pubmed/32455942 http://dx.doi.org/10.3390/molecules25102424 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Barile, Elisa
Baggio, Carlo
Gambini, Luca
Shiryaev, Sergey A.
Strongin, Alex Y.
Pellecchia, Maurizio
Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming
title Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming
title_full Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming
title_fullStr Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming
title_full_unstemmed Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming
title_short Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming
title_sort potential therapeutic targeting of coronavirus spike glycoprotein priming
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287953/
https://www.ncbi.nlm.nih.gov/pubmed/32455942
http://dx.doi.org/10.3390/molecules25102424
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