Dual-Reporter System for Real-Time Monitoring of SARS-CoV-2 Main Protease Activity in Live Cells Enables Identification of an Allosteric Inhibition Path.
- Resource Type
- Academic Journal
- Authors
- Bram Y; Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.; Duan X; Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.; Nilsson-Payant BE; Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustav L Levy Place, New York, New York 10029, United States.; Chandar V; Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.; Wu H; Department of Physiology, Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.; Shore D; Department of Physiology, Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.; Fajardo A; Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.; Sinha S; Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.; Hassan N; Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.; Weinstein H; Department of Physiology, Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.; TenOever BR; Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustav L Levy Place, New York, New York 10029, United States.; Chen S; Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.; Schwartz RE; Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.; Department of Physiology, Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.
- Source
- Publisher: American Chemical Society Country of Publication: United States NLM ID: 9918232604406676 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2694-2437 (Electronic) Linking ISSN: 26942437 NLM ISO Abbreviation: ACS Bio Med Chem Au Subsets: PubMed not MEDLINE
- Subject
- Language
- English
The SARS-CoV-2 pandemic is an ongoing threat to global health, and the continuing emergence of contagious variants highlights the urgent need for additional antiviral therapy to attenuate COVID-19 disease. The SARS-CoV-2 main protease (3CL pro ) presents an attractive target for such therapy due to its high sequence conservation and key role in the viral life cycle. In this study, we designed a fluorescent-luminescent cell-based reporter for the detection and quantification of 3CL pro intracellular activity. Employing this platform, we examined the efficiency of known protease inhibitors against 3CL pro and further identified potent inhibitors through high-throughput chemical screening. Computational analysis confirmed a direct interaction of the lead compounds with the protease catalytic site and identified a prototype for efficient allosteric inhibition. These developments address a pressing need for a convenient sensor and specific targets for both virus detection and rapid discovery of potential inhibitors.
Competing Interests: The authors declare the following competing financial interest(s): R.E.S. is on the scientific advisory board of Miromatrix Inc, and a speaker and consultant for Alnylam Pharmaceuticals.
(© 2022 The Authors. Published by American Chemical Society.)