1. Discovery and Mechanism of SARS-CoV-2 Main Protease Inhibitors
- Author
-
Shaobo Wang, Alex E. Clark, Shashi Kant Tiwari, Tariq M. Rana, Davey M. Smith, Sarah E. Huff, Mark A. Endsley, Matthew B. Huante, Aaron F. Carlin, William Bray, and Indrasena Reddy Kummetha
- Subjects
medicine.medical_treatment ,viruses ,Pharmacology ,Crystallography, X-Ray ,medicine.disease_cause ,Virus Replication ,law.invention ,law ,Drug Discovery ,Chlorocebus aethiops ,Fluorescence Resonance Energy Transfer ,Lung ,Coronavirus 3C Proteases ,Coronavirus ,Crystallography ,medicine.diagnostic_test ,Molecular Structure ,Chemistry ,Pharmacology and Pharmaceutical Sciences ,Molecular Docking Simulation ,Infectious Diseases ,5.1 Pharmaceuticals ,Recombinant DNA ,Pneumonia & Influenza ,Molecular Medicine ,Drug ,Development of treatments and therapeutic interventions ,Proteolysis ,Medicinal & Biomolecular Chemistry ,Drug design ,Microbial Sensitivity Tests ,Cysteine Proteinase Inhibitors ,Antiviral Agents ,Article ,Dose-Response Relationship ,Vaccine Related ,Medicinal and Biomolecular Chemistry ,Biodefense ,medicine ,Organoid ,Animals ,Humans ,Benzothiazoles ,Vero Cells ,Protease ,Dose-Response Relationship, Drug ,SARS-CoV-2 ,Prevention ,Organic Chemistry ,COVID-19 ,Pneumonia ,COVID-19 Drug Treatment ,Good Health and Well Being ,Emerging Infectious Diseases ,Viral replication ,Vero cell ,X-Ray - Abstract
The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant SARS-CoV-2 Mpro identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 Mpro can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit Mpro competitively. Lead E24 inhibited viral replication with a nanomolar EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of Mpro inhibition that should facilitate the design of future COVID-19 treatments.
- Published
- 2021