Journal
ACS CENTRAL SCIENCE
Volume 7, Issue 7, Pages 1245-1260Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscentsci.1c00519
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Funding
- National Institutes of Health (NIH) [AI147325, AI147046]
- Arizona Biomedical Research Centre Young Investigator grant [ADHS18-198859]
- National Institute of General Medical Sciences
- National Institutes of Health [R35 GM128624]
- U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- COVID-19 pilot grant from UTHSCSA
- NIH [AI151638]
- [T32 GM008804]
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The study identified several PLpro inhibitors with improved enzymatic inhibition and antiviral activity, including Jun9-72-2 and Jun9-75-4, through high-throughput screening and lead optimization. The development of a cell-based FlipGFP assay allows for predicting cellular antiviral activity of PLpro inhibitors in the BSL-2 setting. X-ray crystal structure analysis and molecular dynamics simulations provided insights into the interactions of these inhibitors with PLpro.
The papain-like protease (PLpro) of SARS-CoV-2 is a validated antiviral drug target. Through a fluorescence resonance energy transfer-based high-throughput screening and subsequent lead optimization, we identified several PLpro inhibitors including Jun9-72-2 and Jun9-75-4 with improved enzymatic inhibition and antiviral activity compared to GRL0617, which was reported as a SARS-CoV PLpro inhibitor. Significantly, we developed a cell-based FlipGFP assay that can be applied to predict the cellular antiviral activity of PLpro inhibitors in the BSL-2 setting. X-ray crystal structure of PLpro in complex with GRL0617 showed that binding of GRL0617 to SARS-CoV-2 induced a conformational change in the BL2 loop to a more closed conformation. Molecular dynamics simulations showed that Jun9-72-2 and Jun9-75-4 engaged in more extensive interactions than GRL0617. Overall, the PL(pro )inhibitors identified in this study represent promising candidates for further development as SARS-CoV-2 antivirals, and the FlipGFP-PLpro assay is a suitable surrogate for screening PLp inhibitors in the BSL-2 setting.
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