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A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity

The main protease M(pro) of SARS-CoV-2 is a well-studied major drug target. Additionally, it has been linked to this virus’ pathogenicity, possibly through off-target effects. It is also an interesting diagnostic target. To obtain more data on possible substrates as well as to assess the enzyme’s pr...

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Detalles Bibliográficos
Autores principales: Gallo, Gloria, Barcick, Uilla, Coelho, Camila, Salardani, Murilo, Camacho, Maurício F., Cajado-Carvalho, Daniela, Loures, Flávio V., Serrano, Solange M.T., Hardy, Leon, Zelanis, André, Würtele, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134770/
https://www.ncbi.nlm.nih.gov/pubmed/35644302
http://dx.doi.org/10.1016/j.peptides.2022.170814
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author Gallo, Gloria
Barcick, Uilla
Coelho, Camila
Salardani, Murilo
Camacho, Maurício F.
Cajado-Carvalho, Daniela
Loures, Flávio V.
Serrano, Solange M.T.
Hardy, Leon
Zelanis, André
Würtele, Martin
author_facet Gallo, Gloria
Barcick, Uilla
Coelho, Camila
Salardani, Murilo
Camacho, Maurício F.
Cajado-Carvalho, Daniela
Loures, Flávio V.
Serrano, Solange M.T.
Hardy, Leon
Zelanis, André
Würtele, Martin
author_sort Gallo, Gloria
collection PubMed
description The main protease M(pro) of SARS-CoV-2 is a well-studied major drug target. Additionally, it has been linked to this virus’ pathogenicity, possibly through off-target effects. It is also an interesting diagnostic target. To obtain more data on possible substrates as well as to assess the enzyme’s primary specificity a two-step approach was introduced. First, Terminal Amine Isobaric Labeling of Substrates (TAILS) was employed to identify novel M(pro) cleavage sites in a mouse lung proteome library. In a second step, using a structural homology model, the MM/PBSA variant MM/GBSA (Molecular Mechanics Poisson-Boltzmann/Generalized Born Surface Area) free binding energy calculations were carried out to determine relevant interacting amino acids. As a result, 58 unique cleavage sites were detected, including six that displayed glutamine at the P1 position. Furthermore, modeling results indicated that M(pro) has a far higher potential promiscuity towards substrates than expected. The combination of proteomics and MM/PBSA modeling analysis can thus be useful for elucidating the specificity of M(pro), and thus open novel perspectives for the development of future peptidomimetic drugs against COVID-19, as well as diagnostic tools.
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spelling pubmed-91347702022-05-26 A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity Gallo, Gloria Barcick, Uilla Coelho, Camila Salardani, Murilo Camacho, Maurício F. Cajado-Carvalho, Daniela Loures, Flávio V. Serrano, Solange M.T. Hardy, Leon Zelanis, André Würtele, Martin Peptides Article The main protease M(pro) of SARS-CoV-2 is a well-studied major drug target. Additionally, it has been linked to this virus’ pathogenicity, possibly through off-target effects. It is also an interesting diagnostic target. To obtain more data on possible substrates as well as to assess the enzyme’s primary specificity a two-step approach was introduced. First, Terminal Amine Isobaric Labeling of Substrates (TAILS) was employed to identify novel M(pro) cleavage sites in a mouse lung proteome library. In a second step, using a structural homology model, the MM/PBSA variant MM/GBSA (Molecular Mechanics Poisson-Boltzmann/Generalized Born Surface Area) free binding energy calculations were carried out to determine relevant interacting amino acids. As a result, 58 unique cleavage sites were detected, including six that displayed glutamine at the P1 position. Furthermore, modeling results indicated that M(pro) has a far higher potential promiscuity towards substrates than expected. The combination of proteomics and MM/PBSA modeling analysis can thus be useful for elucidating the specificity of M(pro), and thus open novel perspectives for the development of future peptidomimetic drugs against COVID-19, as well as diagnostic tools. Elsevier Inc. 2022-08 2022-05-26 /pmc/articles/PMC9134770/ /pubmed/35644302 http://dx.doi.org/10.1016/j.peptides.2022.170814 Text en © 2022 Elsevier Inc. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Gallo, Gloria
Barcick, Uilla
Coelho, Camila
Salardani, Murilo
Camacho, Maurício F.
Cajado-Carvalho, Daniela
Loures, Flávio V.
Serrano, Solange M.T.
Hardy, Leon
Zelanis, André
Würtele, Martin
A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity
title A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity
title_full A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity
title_fullStr A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity
title_full_unstemmed A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity
title_short A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity
title_sort proteomics-mm/pbsa dual approach for the analysis of sars-cov-2 main protease substrate peptide specificity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134770/
https://www.ncbi.nlm.nih.gov/pubmed/35644302
http://dx.doi.org/10.1016/j.peptides.2022.170814
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