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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Published inInternational journal of molecular sciences Vol. 24; no. 7; p. 6062
Main Authors 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
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 23.03.2023
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Abstract 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.
AbstractList 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.
Audience Academic
Author Mariani, Paolo
Sabbatini, Samuele
Schiaroli, Elisabetta
Comez, Lucia
Belhaj, Norhan
Silvestrini, Lucia
Libera, Valeria
Macchiarulo, Antonio
Spinozzi, Francesco
Orecchini, Andrea
Petrillo, Caterina
Paciaroni, Alessandro
Gidari, Anna
Ripanti, Francesca
Roque, Yessica
Moretti, Paolo
Vercelli, Matteo
Bianconi, Elisa
Hussain, Rohanah
Francisci, Daniela
AuthorAffiliation 5 Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 06123 Perugia, Italy
4 Department of Medicine and Surgery, Medical Microbiology Section, University of Perugia, Piazzale Gambuli, 06129 Perugia, Italy
3 Department of Medicine and Surgery, Clinic of Infectious Diseases, University of Perugia, Piazzale Gambuli, 06129 Perugia, Italy
6 Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
2 Istituto Officina dei Materiali-IOM, National Research Council-CNR, Via Alessandro Pascoli, 06123 Perugia, Italy
7 Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 12, 60131 Ancona, Italy
1 Department of Physics and Geology, University of Perugia, Via Alessandro Pascoli, 06123 Perugia, Italy
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Issue 7
Keywords COVID-19
Paxlovid
SARS-CoV-2
inhibitor
main protease
dimerization
microscale thermophoresis
circular dichroism
PF-07321332
small angle X-ray scattering
Language English
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Snippet 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...
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SubjectTerms Antiviral activity
Antiviral agents
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Binding
Binding sites
Bioavailability
Catalytic activity
Coronaviridae
Coronaviruses
COVID-19
COVID-19 vaccines
Cysteine Endopeptidases - metabolism
Dimerization
Drug development
Drugs
Enzymes
Equilibrium
Feline infectious peritonitis
Health aspects
Humans
Hydrogen
Hydrogen bonding
Hydrogen bonds
Infections
inhibitor
Inhibitors
Ligands
main protease
Middle East respiratory syndrome
Molecular Docking Simulation
Paxlovid
Peritonitis
Polyproteins
Protease
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Proteases
Proteinase
Proteinase inhibitors
Proteins
Respiratory diseases
SARS-CoV-2
SARS-CoV-2 - metabolism
Severe acute respiratory syndrome coronavirus 2
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Title Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir
URI https://www.ncbi.nlm.nih.gov/pubmed/37047038
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https://pubmed.ncbi.nlm.nih.gov/PMC10093836
https://doaj.org/article/6d4986a6df1b4a0089b26d2cdcbacc33
Volume 24
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