3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV–infected mice

Rathnayake, Athri D.; Zheng, Jian; Kim, Yunjeong; Perera, Krishani Dinali; Mackin, Samantha; Meyerholz, David K.; Kashipathy, Maithri M.; Battaile, Kevin P.; Lovell, Scott; Perlman, Stanley; Groutas, William C.; Chang, Kyeong-Ok

doi:10.1126/scitranslmed.abc5332

3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV–infected mice

Journal Article · Wed Aug 19 00:00:00 EDT 2020 · Science Translational Medicine

DOI:https://doi.org/10.1126/scitranslmed.abc5332· OSTI ID:1661001

^[1]; ^[2]; ^[3]; ^[3]; Mackin, Samantha ^[2]; ^[2]; ^[4]; ^[5]; ^[4]; ^[2]; ^[1]; ^[3]

Wichita State Univ., Wichita, KS (United States)
Univ. of Iowa, Iowa City, IA (United States)
Kansas State Univ., Manhattan, KS (United States)
Univ. of Kansas, Lawrence, KS (United States)
New York Structural Biology Center, Upton, NY (United States)

Pathogenic coronaviruses are a major threat to global public health, as exemplified by severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emerged SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). We describe herein the structure-guided optimization of a series of inhibitors of the coronavirus 3C-like protease (3CLpro), an enzyme essential for viral replication. The optimized compounds were effective against several human coronaviruses including MERS-CoV, SARS-CoV, and SARS-CoV-2 in an enzyme assay and in cell-based assays using Huh-7 and Vero E6 cell lines. Two selected compounds showed antiviral effects against SARS-CoV-2 in cultured primary human airway epithelial cells. In a mouse model of MERS-CoV infection, administration of a lead compound 1 day after virus infection increased survival from 0 to 100% and reduced lung viral titers and lung histopathology. These results suggest that this series of compounds has the potential to be developed further as antiviral drugs against human coronaviruses.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1661001

Journal Information:: Science Translational Medicine, Journal Name: Science Translational Medicine Journal Issue: 557 Vol. 12; ISSN 1946-6234

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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