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 in:	International 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
Language:	English
Published:	Switzerland MDPI AG 23-03-2023 MDPI
Subjects:	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 Germany Middle East COVID-19 Paxlovid SARS-CoV-2 inhibitor main protease dimerization microscale thermophoresis circular dichroism PF-07321332 small angle X-ray scattering
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms24076062