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

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 Lee, Charles Karan, Samuel J. Resnick, Colette Quinn, Wenjing Li, Henry Shion, Xin Xia, Jacob D. Daniels, Michelle Bartolo-Cruz, Marcelo Farina, Presha Rajbhandari, Christopher Jurtschenko, Matthew A. Lauber, Thomas McDonald, Michael E. Stokes, Brett L. Hurst, Tomislav Rovis (), Alejandro Chavez (), David D. Ho () and Brent R. Stockwell ()
Additional contact information
Hengrui Liu: Columbia University
Sho Iketani: 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
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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

Date: 2022
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DOI: 10.1038/s41467-022-29413-2

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