Journal
SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-88630-9
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Funding
- European Union [823780]
- Marie Curie Actions (MSCA) [823780] Funding Source: Marie Curie Actions (MSCA)
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The study investigated the structural features and thermodynamics of the SARS-CoV-2 M-pro protein using Small Angle X-ray Scattering (SAXS), providing key information for therapeutic intervention. It was found that small molecule inhibitors can affect dimerization and enzymatic activity of M-pro to varying extents, potentially serving as leads for antiviral drug development.
The maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease M-pro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the M-pro monomer-dimer equilibrium dissociation constant. Since the functional unit of M-pro 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 M-pro 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 M-pro 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 M-pro residues that emerge as key to optimize both dissociation and enzymatic activity inhibition are discussed.
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