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Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike

There are no approved target therapeutics against SARS-CoV-2 or other beta-CoVs. The beta-CoV Spike protein is a promising target considering the critical role in viral infection and pathogenesis and its surface exposed features. We performed a structure-based strategy targeting highly conserved dru...

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Autores principales: Trigueiro-Louro, João, Correia, Vanessa, Figueiredo-Nunes, Inês, Gíria, Marta, Rebelo-de-Andrade, Helena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Research Network of Computational and Structural Biotechnology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452956/
https://www.ncbi.nlm.nih.gov/pubmed/32913581
http://dx.doi.org/10.1016/j.csbj.2020.07.017
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author Trigueiro-Louro, João
Correia, Vanessa
Figueiredo-Nunes, Inês
Gíria, Marta
Rebelo-de-Andrade, Helena
author_facet Trigueiro-Louro, João
Correia, Vanessa
Figueiredo-Nunes, Inês
Gíria, Marta
Rebelo-de-Andrade, Helena
author_sort Trigueiro-Louro, João
collection PubMed
description There are no approved target therapeutics against SARS-CoV-2 or other beta-CoVs. The beta-CoV Spike protein is a promising target considering the critical role in viral infection and pathogenesis and its surface exposed features. We performed a structure-based strategy targeting highly conserved druggable regions resulting from a comprehensive large-scale sequence analysis and structural characterization of Spike domains across SARSr- and MERSr-CoVs. We have disclosed 28 main consensus druggable pockets within the Spike. The RBD and SD1 (S1 subunit); and the CR, HR1 and CH (S2 subunit) represent the most promising conserved druggable regions. Additionally, we have identified 181 new potential hot spot residues for the hSARSr-CoVs and 72 new hot spot residues for the SARSr- and MERSr-CoVs, which have not been described before in the literature. These sites/residues exhibit advantageous structural features for targeted molecular and pharmacological modulation. This study establishes the Spike as a promising anti-CoV target using an approach with a potential higher resilience to resistance development and directed to a broad spectrum of Beta-CoVs, including the new SARS-CoV-2 responsible for COVID-19. This research also provides a structure-based rationale for the design and discovery of chemical inhibitors, antibodies or other therapeutic modalities successfully targeting the Beta-CoV Spike protein.
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spelling pubmed-74529562020-09-09 Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike Trigueiro-Louro, João Correia, Vanessa Figueiredo-Nunes, Inês Gíria, Marta Rebelo-de-Andrade, Helena Comput Struct Biotechnol J Research Article There are no approved target therapeutics against SARS-CoV-2 or other beta-CoVs. The beta-CoV Spike protein is a promising target considering the critical role in viral infection and pathogenesis and its surface exposed features. We performed a structure-based strategy targeting highly conserved druggable regions resulting from a comprehensive large-scale sequence analysis and structural characterization of Spike domains across SARSr- and MERSr-CoVs. We have disclosed 28 main consensus druggable pockets within the Spike. The RBD and SD1 (S1 subunit); and the CR, HR1 and CH (S2 subunit) represent the most promising conserved druggable regions. Additionally, we have identified 181 new potential hot spot residues for the hSARSr-CoVs and 72 new hot spot residues for the SARSr- and MERSr-CoVs, which have not been described before in the literature. These sites/residues exhibit advantageous structural features for targeted molecular and pharmacological modulation. This study establishes the Spike as a promising anti-CoV target using an approach with a potential higher resilience to resistance development and directed to a broad spectrum of Beta-CoVs, including the new SARS-CoV-2 responsible for COVID-19. This research also provides a structure-based rationale for the design and discovery of chemical inhibitors, antibodies or other therapeutic modalities successfully targeting the Beta-CoV Spike protein. Research Network of Computational and Structural Biotechnology 2020-07-31 /pmc/articles/PMC7452956/ /pubmed/32913581 http://dx.doi.org/10.1016/j.csbj.2020.07.017 Text en © 2020 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Trigueiro-Louro, João
Correia, Vanessa
Figueiredo-Nunes, Inês
Gíria, Marta
Rebelo-de-Andrade, Helena
Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike
title Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike
title_full Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike
title_fullStr Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike
title_full_unstemmed Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike
title_short Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike
title_sort unlocking covid therapeutic targets: a structure-based rationale against sars-cov-2, sars-cov and mers-cov spike
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452956/
https://www.ncbi.nlm.nih.gov/pubmed/32913581
http://dx.doi.org/10.1016/j.csbj.2020.07.017
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