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Volume 12
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10.3390/pathogens12020324
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Article

Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors

by
Marion Schuller
1,*,
Tryfon Zarganes-Tzitzikas
2,
James Bennett
2,
Stephane De Cesco
2,
Daren Fearon
3,4,
Frank von Delft
2,3,4,5,6,
Oleg Fedorov
2,
Paul E. Brennan
2 and
Ivan Ahel
1,*
1
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
2
Centre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UK
3
Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
4
Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK
5
Structural Genomics Consortium, University of Oxford, Headington OX3 7DQ, UK
6
Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa
*
Authors to whom correspondence should be addressed.
Pathogens 2023, 12(2), 324; https://doi.org/10.3390/pathogens12020324
Submission received: 12 January 2023 / Revised: 3 February 2023 / Accepted: 10 February 2023 / Published: 15 February 2023
(This article belongs to the Special Issue ADP-Ribosylation in Pathogens)
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Abstract

The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibiotic compound aztreonam, to the active site of the macrodomain provide valuable structure–activity relationship information that support current approaches and open up new avenues for NSP3 macrodomain inhibitor development.
Keywords: ADP-ribosylation; macrodomain; SARS-CoV-2; COVID-19; non-structural protein 3 (NSP3); drug discovery and development; virtual screening ADP-ribosylation; macrodomain; SARS-CoV-2; COVID-19; non-structural protein 3 (NSP3); drug discovery and development; virtual screening

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MDPI and ACS Style

Schuller, M.; Zarganes-Tzitzikas, T.; Bennett, J.; De Cesco, S.; Fearon, D.; von Delft, F.; Fedorov, O.; Brennan, P.E.; Ahel, I. Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors. Pathogens 2023, 12, 324. https://doi.org/10.3390/pathogens12020324

AMA Style

Schuller M, Zarganes-Tzitzikas T, Bennett J, De Cesco S, Fearon D, von Delft F, Fedorov O, Brennan PE, Ahel I. Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors. Pathogens. 2023; 12(2):324. https://doi.org/10.3390/pathogens12020324

Chicago/Turabian Style

Schuller, Marion, Tryfon Zarganes-Tzitzikas, James Bennett, Stephane De Cesco, Daren Fearon, Frank von Delft, Oleg Fedorov, Paul E. Brennan, and Ivan Ahel. 2023. "Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors" Pathogens 12, no. 2: 324. https://doi.org/10.3390/pathogens12020324

APA Style

Schuller, M., Zarganes-Tzitzikas, T., Bennett, J., De Cesco, S., Fearon, D., von Delft, F., Fedorov, O., Brennan, P. E., & Ahel, I. (2023). Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors. Pathogens, 12(2), 324. https://doi.org/10.3390/pathogens12020324

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