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

Journal Article · · Nature Communications
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  1. Columbia Univ., New York, NY (United States)
  2. Columbia Univ., New York, NY (United States). Irving Medical Center
  3. Waters Corporation, Milford, MA (United States)
  4. Columbia Univ., New York, NY (United States); Universidade Federal de Santa Catarina (UFSC), Florianopolis, SC (Brazil)
  5. Utah State Univ., Logan, UT (United States)
+ Show Author Affiliations

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 <10nM 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC); National Institutes of Health (NIH); National Science Foundation (NSF)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1866444
Alternate ID(s):
OSTI ID: 1869885
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 13; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Related Subjects

60 APPLIED LIFE SCIENCES
lead optimization
proteases
small molecules