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Research Article
Francesco Spinozzi
Marche Polytechnic University
Corresponding Author
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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 the SARS-CoV-2 Mpro monomer-dimer equilibrium, by revealing the corresponding equilibrium dissociation constant and the associated thermodynamic parameters. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected through combinatorial design. Our results show that a clear picture connecting the ability of inhibitors to disrupt the Mpro dimerization with the loss of catalytic activity cannot be provided, thus highlighting the possible role of allosteric effects for the regulation of Mpro functionality.
Keywords
COVID-19 pandemic, SARS-CoV-2, SAXS
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Posted 13 Jan, 2021
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On 19 Jan, 2021
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This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Francesco Spinozzi
Marche Polytechnic University
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 13 Jan, 2021
No community comments so far
Editorial decision: Major revision
On 16 Feb, 2021
Reviews received
Received 29 Jan, 2021
Reviewers agreed
On 19 Jan, 2021
Reviewers agreed
On 19 Jan, 2021
Reviewers invited
Invitations sent on 19 Jan, 2021
Editor assigned
On 06 Jan, 2021
Editor invited
On 06 Jan, 2021
Submission checks complete
On 06 Jan, 2021
First submitted
On 23 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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 the SARS-CoV-2 Mpro monomer-dimer equilibrium, by revealing the corresponding equilibrium dissociation constant and the associated thermodynamic parameters. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected through combinatorial design. Our results show that a clear picture connecting the ability of inhibitors to disrupt the Mpro dimerization with the loss of catalytic activity cannot be provided, thus highlighting the possible role of allosteric effects for the regulation of Mpro functionality.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
This preprint is available for download as a PDF.
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