2. Academic Validation
  3. Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19

Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19

  • Nat Commun. 2022 Apr 7;13(1):1891. doi: 10.1038/s41467-022-29413-2.
Hengrui Liu 1,  Sho Iketani 2 3,  Arie Zask 4,  Nisha Khanizeman 1,  Eva Bednarova 1,  Farhad Forouhar 5,  Brandon Fowler 1,  Seo Jung Hong 6,  Hiroshi Mohri 2,  Manoj S Nair 2,  Yaoxing Huang 2,  Nicholas E S Tay 1,  Sumin Lee 1,  Charles Karan 7,  Samuel J Resnick 6 8,  Colette Quinn 9,  Wenjing Li 9,  Henry Shion 9,  Xin Xia 4,  Jacob D Daniels 10,  Michelle Bartolo-Cruz 4,  Marcelo Farina 4 11,  Presha Rajbhandari 4,  Christopher Jurtschenko 9,  Matthew A Lauber 9,  Thomas McDonald 9,  Michael E Stokes 4,  Brett L Hurst 12,  Tomislav Rovis 13,  Alejandro Chavez 14,  David D Ho 15,  Brent R Stockwell 16 17
Affiliations

Affiliations

  • 1 Department of Chemistry, Columbia University, New York, NY, 10027, USA.
  • 2 Aaron Diamond AIDS Research Center, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • 3 Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • 4 Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.
  • 5 Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • 6 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • 7 Sulzberger Columbia Genome Center, Columbia University, New York, NY, 10032, USA.
  • 8 Medical Scientist Training Program, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • 9 Waters Corporation, 34 Maple Street, Milford, MA, 01757, USA.
  • 10 Department of Pharmacology and Molecular Therapeutics, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • 11 Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil.
  • 12 Institute for Antiviral Research, Utah State University, Logan, UT, 84322, USA.
  • 13 Department of Chemistry, Columbia University, New York, NY, 10027, USA. tr2504@columbia.edu.
  • 14 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA. ac4304@cumc.columbia.edu.
  • 15 Aaron Diamond AIDS Research Center, Columbia University Irving Medical Center, New York, NY, 10032, USA. dh2994@cumc.columbia.edu.
  • 16 Department of Chemistry, Columbia University, New York, NY, 10027, USA. bstockwell@columbia.edu.
  • 17 Department of Biological Sciences, Columbia University, New York, NY, 10027, USA. bstockwell@columbia.edu.
PMID: 35393402 DOI: 10.1038/s41467-022-29413-2
Abstract

The SARS-CoV-2 3CL Protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL Protease Substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL Protease. After evaluation of their binding specificity, cellular Antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL Protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule Protease inhibitor for the treatment of SARS-CoV-2 Infection for eliminating pandemics involving coronaviruses.

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