Discovery and development strategies for SARS-CoV-2 NSP3 macrodomain inhibitors

DOI: 10.3390/pathogens12020324

Authors: Marion Schuller (University of Oxford) , Tryfon Zarganes-Tzitzikas (University of Oxford) , James Bennett (University of Oxford) , Stephane De Cesco (University of Oxford) , Daren Fearon (Diamond Light Source; Research Complex at Harwell) , Frank Von Delft (Structural Genomics Consortium, University of Oxford; Diamond Light Source; Research Complex at Harwell; University of Johannesburg) , Oleg Fedorov (University of Oxford) , Paul E. Brennan (University of Oxford) , Ivan Ahel (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Pathogens , VOL 12

State: Published (Approved)
Published: February 2023
Diamond Proposal Number(s): 23459

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.

Journal Keywords: ADP-ribosylation; macrodomain; SARS-CoV-2; COVID-19; non-structural protein 3 (NSP3); drug discovery and development; virtual screening

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 22/02/2023 08:34

Documents:
pathogens-12-00324-v2.pdf

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)