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Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir
The main protease (Mpro or 3CLpro) is an enzyme that is evolutionarily conserved among different genera of coronaviruses. As it is essential for processing and maturing viral polyproteins, Mpro has been identified as a promising target for the development of broad-spectrum drugs against coronaviruse...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093836/ https://www.ncbi.nlm.nih.gov/pubmed/37047038 http://dx.doi.org/10.3390/ijms24076062 |
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author | Paciaroni, Alessandro Libera, Valeria Ripanti, Francesca Orecchini, Andrea Petrillo, Caterina Francisci, Daniela Schiaroli, Elisabetta Sabbatini, Samuele Gidari, Anna Bianconi, Elisa Macchiarulo, Antonio Hussain, Rohanah Silvestrini, Lucia Moretti, Paolo Belhaj, Norhan Vercelli, Matteo Roque, Yessica Mariani, Paolo Comez, Lucia Spinozzi, Francesco |
author_facet | Paciaroni, Alessandro Libera, Valeria Ripanti, Francesca Orecchini, Andrea Petrillo, Caterina Francisci, Daniela Schiaroli, Elisabetta Sabbatini, Samuele Gidari, Anna Bianconi, Elisa Macchiarulo, Antonio Hussain, Rohanah Silvestrini, Lucia Moretti, Paolo Belhaj, Norhan Vercelli, Matteo Roque, Yessica Mariani, Paolo Comez, Lucia Spinozzi, Francesco |
author_sort | Paciaroni, Alessandro |
collection | PubMed |
description | The main protease (Mpro or 3CLpro) is an enzyme that is evolutionarily conserved among different genera of coronaviruses. As it is essential for processing and maturing viral polyproteins, Mpro has been identified as a promising target for the development of broad-spectrum drugs against coronaviruses. Like SARS-CoV and MERS-CoV, the mature and active form of SARS-CoV-2 Mpro is a dimer composed of identical subunits, each with a single active site. Individual monomers, however, have very low or no catalytic activity. As such, inhibition of Mpro can be achieved by molecules that target the substrate binding pocket to block catalytic activity or target the dimerization process. In this study, we investigated GC376, a transition-state analog inhibitor of the main protease of feline infectious peritonitis coronavirus, and Nirmatrelvir (NMV), an oral, bioavailable SARS-CoV-2 Mpro inhibitor with pan-human coronavirus antiviral activity. Our results show that both GC376 and NMV are capable of strongly binding to SARS-CoV-2 Mpro and altering the monomer-dimer equilibrium by stabilizing the dimeric state. This behavior is proposed to be related to a structured hydrogen-bond network established at the Mpro active site, where hydrogen bonds between Ser1’ and Glu166/Phe140 are formed in addition to those achieved by the latter residues with GC376 or NMV. |
format | Online Article Text |
id | pubmed-10093836 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100938362023-04-13 Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir Paciaroni, Alessandro Libera, Valeria Ripanti, Francesca Orecchini, Andrea Petrillo, Caterina Francisci, Daniela Schiaroli, Elisabetta Sabbatini, Samuele Gidari, Anna Bianconi, Elisa Macchiarulo, Antonio Hussain, Rohanah Silvestrini, Lucia Moretti, Paolo Belhaj, Norhan Vercelli, Matteo Roque, Yessica Mariani, Paolo Comez, Lucia Spinozzi, Francesco Int J Mol Sci Article The main protease (Mpro or 3CLpro) is an enzyme that is evolutionarily conserved among different genera of coronaviruses. As it is essential for processing and maturing viral polyproteins, Mpro has been identified as a promising target for the development of broad-spectrum drugs against coronaviruses. Like SARS-CoV and MERS-CoV, the mature and active form of SARS-CoV-2 Mpro is a dimer composed of identical subunits, each with a single active site. Individual monomers, however, have very low or no catalytic activity. As such, inhibition of Mpro can be achieved by molecules that target the substrate binding pocket to block catalytic activity or target the dimerization process. In this study, we investigated GC376, a transition-state analog inhibitor of the main protease of feline infectious peritonitis coronavirus, and Nirmatrelvir (NMV), an oral, bioavailable SARS-CoV-2 Mpro inhibitor with pan-human coronavirus antiviral activity. Our results show that both GC376 and NMV are capable of strongly binding to SARS-CoV-2 Mpro and altering the monomer-dimer equilibrium by stabilizing the dimeric state. This behavior is proposed to be related to a structured hydrogen-bond network established at the Mpro active site, where hydrogen bonds between Ser1’ and Glu166/Phe140 are formed in addition to those achieved by the latter residues with GC376 or NMV. MDPI 2023-03-23 /pmc/articles/PMC10093836/ /pubmed/37047038 http://dx.doi.org/10.3390/ijms24076062 Text en © 2023 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 Paciaroni, Alessandro Libera, Valeria Ripanti, Francesca Orecchini, Andrea Petrillo, Caterina Francisci, Daniela Schiaroli, Elisabetta Sabbatini, Samuele Gidari, Anna Bianconi, Elisa Macchiarulo, Antonio Hussain, Rohanah Silvestrini, Lucia Moretti, Paolo Belhaj, Norhan Vercelli, Matteo Roque, Yessica Mariani, Paolo Comez, Lucia Spinozzi, Francesco Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir |
title | Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir |
title_full | Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir |
title_fullStr | Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir |
title_full_unstemmed | Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir |
title_short | Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir |
title_sort | stabilization of the dimeric state of sars-cov-2 main protease by gc376 and nirmatrelvir |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093836/ https://www.ncbi.nlm.nih.gov/pubmed/37047038 http://dx.doi.org/10.3390/ijms24076062 |
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