The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

Abstract The maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro...

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Autores principales:	Lucia Silvestrini, Norhan Belhaj, Lucia Comez, Yuri Gerelli, Antonino Lauria, Valeria Libera, Paolo Mariani, Paola Marzullo, Maria Grazia Ortore, Antonio Palumbo Piccionello, Caterina Petrillo, Lucrezia Savini, Alessandro Paciaroni, Francesco Spinozzi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/02bfcfccb4f9426583834a691e65e91b
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spelling	oai:doaj.org-article:02bfcfccb4f9426583834a691e65e91b2021-12-02T17:20:12ZThe dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors10.1038/s41598-021-88630-92045-2322https://doaj.org/article/02bfcfccb4f9426583834a691e65e91b2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88630-9https://doaj.org/toc/2045-2322Abstract The maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit Small Angle X-ray Scattering (SAXS) to investigate the structural features of SARS-CoV-2 Mpro in solution as a function of protein concentration and temperature. A detailed thermodynamic picture of the monomer-dimer equilibrium is derived, together with the temperature-dependent value of the dissociation constant. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected by virtual screening. We find that these inhibitors affect dimerization and enzymatic activity to a different extent and sometimes in an opposite way, likely due to the different molecular mechanisms underlying the two processes. The Mpro residues that emerge as key to optimize both dissociation and enzymatic activity inhibition are discussed.Lucia SilvestriniNorhan BelhajLucia ComezYuri GerelliAntonino LauriaValeria LiberaPaolo MarianiPaola MarzulloMaria Grazia OrtoreAntonio Palumbo PiccionelloCaterina PetrilloLucrezia SaviniAlessandro PaciaroniFrancesco SpinozziNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lucia Silvestrini Norhan Belhaj Lucia Comez Yuri Gerelli Antonino Lauria Valeria Libera Paolo Mariani Paola Marzullo Maria Grazia Ortore Antonio Palumbo Piccionello Caterina Petrillo Lucrezia Savini Alessandro Paciaroni Francesco Spinozzi The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors
description	Abstract The maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit Small Angle X-ray Scattering (SAXS) to investigate the structural features of SARS-CoV-2 Mpro in solution as a function of protein concentration and temperature. A detailed thermodynamic picture of the monomer-dimer equilibrium is derived, together with the temperature-dependent value of the dissociation constant. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected by virtual screening. We find that these inhibitors affect dimerization and enzymatic activity to a different extent and sometimes in an opposite way, likely due to the different molecular mechanisms underlying the two processes. The Mpro residues that emerge as key to optimize both dissociation and enzymatic activity inhibition are discussed.
format	article
author	Lucia Silvestrini Norhan Belhaj Lucia Comez Yuri Gerelli Antonino Lauria Valeria Libera Paolo Mariani Paola Marzullo Maria Grazia Ortore Antonio Palumbo Piccionello Caterina Petrillo Lucrezia Savini Alessandro Paciaroni Francesco Spinozzi
author_facet	Lucia Silvestrini Norhan Belhaj Lucia Comez Yuri Gerelli Antonino Lauria Valeria Libera Paolo Mariani Paola Marzullo Maria Grazia Ortore Antonio Palumbo Piccionello Caterina Petrillo Lucrezia Savini Alessandro Paciaroni Francesco Spinozzi
author_sort	Lucia Silvestrini
title	The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors
title_short	The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors
title_full	The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors
title_fullStr	The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors
title_full_unstemmed	The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors
title_sort	dimer-monomer equilibrium of sars-cov-2 main protease is affected by small molecule inhibitors
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/02bfcfccb4f9426583834a691e65e91b
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The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

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