Cell Reports (Nov 2024)
An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo
- Nian E. Zhou,
- Su Tang,
- Xuelin Bian,
- Maloy K. Parai,
- Inna V. Krieger,
- Armando Flores,
- Pradeep K. Jaiswal,
- Radha Bam,
- Jeremy L. Wood,
- Zhe Shi,
- Laura J. Stevens,
- Trevor Scobey,
- Meghan V. Diefenbacher,
- Fernando R. Moreira,
- Thomas J. Baric,
- Arjun Acharya,
- Joonyoung Shin,
- Manish M. Rathi,
- Karen C. Wolff,
- Laura Riva,
- Malina A. Bakowski,
- Case W. McNamara,
- Nicholas J. Catanzaro,
- Rachel L. Graham,
- David C. Schultz,
- Sara Cherry,
- Yoshihiro Kawaoka,
- Peter J. Halfmann,
- Ralph S. Baric,
- Mark R. Denison,
- Timothy P. Sheahan,
- James C. Sacchettini
Affiliations
- Nian E. Zhou
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Su Tang
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Xuelin Bian
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Maloy K. Parai
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Inna V. Krieger
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Armando Flores
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Pradeep K. Jaiswal
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Radha Bam
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Jeremy L. Wood
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Zhe Shi
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Laura J. Stevens
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
- Trevor Scobey
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Meghan V. Diefenbacher
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Fernando R. Moreira
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Thomas J. Baric
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Arjun Acharya
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Joonyoung Shin
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Manish M. Rathi
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA
- Karen C. Wolff
- Calibr-Skaggs Institute for Innovative Medicine, La Jolla, CA 92037, USA
- Laura Riva
- Calibr-Skaggs Institute for Innovative Medicine, La Jolla, CA 92037, USA
- Malina A. Bakowski
- Calibr-Skaggs Institute for Innovative Medicine, La Jolla, CA 92037, USA
- Case W. McNamara
- Calibr-Skaggs Institute for Innovative Medicine, La Jolla, CA 92037, USA
- Nicholas J. Catanzaro
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Rachel L. Graham
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- David C. Schultz
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA
- Sara Cherry
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Yoshihiro Kawaoka
- Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA
- Peter J. Halfmann
- Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA
- Ralph S. Baric
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Mark R. Denison
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
- Timothy P. Sheahan
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Corresponding author
- James C. Sacchettini
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 11
p. 114929
Abstract
Summary: Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry. NZ-804 potently inhibits SARS-CoV-2 Mpro (0.009 μM IC50) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM EC50) and primary human airway epithelial cell cultures. Antiviral activity is maintained against distantly related sarbecoviruses and endemic human CoV OC43. In SARS-CoV-2 mouse and hamster disease models, NZ-804 therapy given once or twice daily significantly diminished SARS-CoV-2 replication and pathogenesis. NZ-804 synthesis is low cost and uncomplicated, simplifying global production and access. These data support the exploration of NZ-804 as a therapy for COVID-19 and future emerging sarbecovirus infections.
