Download MendeleyDiscovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay.
Ma, C., Sacco, M.D., Xia, Z., Lambrinidis, G., Townsend, J.A., Hu, Y., Meng, X., Szeto, T., Ba, M., Zhang, X., Gongora, M., Zhang, F., Marty, M.T., Xiang, Y., Kolocouris, A., Chen, Y., Wang, J.(2021) ACS Cent Sci 7: 1245-1260
- PubMed: 34341772
- DOI: https://doi.org/10.1021/acscentsci.1c00519
- Primary Citation of Related Structures:
7JRN - PubMed Abstract:
The papain-like protease (PL pro ) 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 PL pro 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 PL pro inhibitor. Significantly, we developed a cell-based FlipGFP assay that can be applied to predict the cellular antiviral activity of PL pro inhibitors in the BSL-2 setting. X-ray crystal structure of PL pro 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-PL pro assay is a suitable surrogate for screening PL pro inhibitors in the BSL-2 setting.
Organizational Affiliation:
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
