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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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