3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice
Rathnayake, Athri D.
Perera, Krishani Dinali
MacKin, Samantha R.
Meyerholz, David K.
Kashipathy, Maithri M.
Battaile, Kevin P.
Groutas, William C.
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Jian; Kim, Yunjeong; Perera, Krishani Dinali; MacKin, Samantha R.; Meyerholz, David K.; Kashipathy, Maithri M.; Battaile, Kevin P.; Lovell, Scott; Perlman, Stanley; Groutas, William C.; Chang, Kyeong-Ok. 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice. Science translational medicine, vol. 12:no. 557
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.
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.