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

Author

Listed:
  • Hengrui Liu

    (Columbia University)

  • Sho Iketani

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

  • Arie Zask

    (Columbia University)

  • Nisha Khanizeman

    (Columbia University)

  • Eva Bednarova

    (Columbia University)

  • Farhad Forouhar

    (Columbia University Irving Medical Center)

  • Brandon Fowler

    (Columbia University)

  • Seo Jung Hong

    (Columbia University Irving Medical Center)

  • Hiroshi Mohri

    (Columbia University Irving Medical Center)

  • Manoj S. Nair

    (Columbia University Irving Medical Center)

  • Yaoxing Huang

    (Columbia University Irving Medical Center)

  • Nicholas E. S. Tay

    (Columbia University)

  • Sumin Lee

    (Columbia University)

  • Charles Karan

    (Columbia University)

  • Samuel J. Resnick

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

  • Colette Quinn

    (Waters Corporation)

  • Wenjing Li

    (Waters Corporation)

  • Henry Shion

    (Waters Corporation)

  • Xin Xia

    (Columbia University)

  • Jacob D. Daniels

    (Columbia University Irving Medical Center)

  • Michelle Bartolo-Cruz

    (Columbia University)

  • Marcelo Farina

    (Columbia University
    Federal University of Santa Catarina)

  • Presha Rajbhandari

    (Columbia University)

  • Christopher Jurtschenko

    (Waters Corporation)

  • Matthew A. Lauber

    (Waters Corporation)

  • Thomas McDonald

    (Waters Corporation)

  • Michael E. Stokes

    (Columbia University)

  • Brett L. Hurst

    (Utah State University)

  • Tomislav Rovis

    (Columbia University)

  • Alejandro Chavez

    (Columbia University Irving Medical Center)

  • David D. Ho

    (Columbia University Irving Medical Center)

  • Brent R. Stockwell

    (Columbia University
    Columbia University)

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

Suggested Citation

  • Hengrui Liu & Sho Iketani & Arie Zask & Nisha Khanizeman & Eva Bednarova & Farhad Forouhar & Brandon Fowler & Seo Jung Hong & Hiroshi Mohri & Manoj S. Nair & Yaoxing Huang & Nicholas E. S. Tay & Sumin, 2022. "Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29413-2
    DOI: 10.1038/s41467-022-29413-2
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    1. Brian C. Sanders & Suman Pokhrel & Audrey D. Labbe & Irimpan I. Mathews & Connor J. Cooper & Russell B. Davidson & Gwyndalyn Phillips & Kevin L. Weiss & Qiu Zhang & Hugh O’Neill & Manat Kaur & Jurgen , 2023. "Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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