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

DOI: 10.1038/s41598-021-88630-9 DOI Help

Authors: Lucia Silvestrini (Marche Polytechnic University) , Norhan Belhaj (Marche Polytechnic University) , Lucia Comez (CNR-IOM c/o University of Perugia) , Yuri Gerelli (Marche Polytechnic University) , Antonino Lauria (University of Palermo) , Valeria Libera (University of Perugia) , Paolo Mariani (Marche Polytechnic University) , Paola Marzullo (University of Palermo) , Maria Grazia Ortore (Marche Polytechnic University) , Antonio Palumbo Piccionello (University of Palermo) , Caterina Petrillo (University of Perugia) , Lucrezia Savini (Marche Polytechnic University) , Alessandro Paciaroni (University of Perugia) , Francesco Spinozzi (Marche Polytechnic University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 11

State: Published (Approved)
Published: April 2021
Diamond Proposal Number(s): 27078

Open Access Open Access

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.

Journal Keywords: Biophysics; Computational biology and bioinformatics; Drug discovery; Molecular biology

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B21-High Throughput SAXS

Added On: 06/05/2021 10:11

Documents:
s41598-021-88630-9.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)