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

Autor:	Rathnayake AD; Department of Chemistry, Wichita State University, Wichita, KS 67260, USA., Zheng J; Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA., Kim Y; Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA., Perera KD; Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA., Mackin S; Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA., Meyerholz DK; Department of Pathology, University of Iowa, Iowa City, IA 52242, USA., Kashipathy MM; Protein Structure Laboratory, University of Kansas, Lawrence, KS 66045, USA., Battaile KP; NYX, New York Structural Biology Center, Upton, NY 11973, USA., Lovell S; Protein Structure Laboratory, University of Kansas, Lawrence, KS 66045, USA., Perlman S; Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA. kchang@vet.ksu.edu stanley-perlman@uiowa.edu bill.groutas@wichita.edu., Groutas WC; Department of Chemistry, Wichita State University, Wichita, KS 67260, USA. kchang@vet.ksu.edu stanley-perlman@uiowa.edu bill.groutas@wichita.edu., Chang KO; Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA. kchang@vet.ksu.edu stanley-perlman@uiowa.edu bill.groutas@wichita.edu.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2020 Aug 19; Vol. 12 (557). Date of Electronic Publication: 2020 Aug 03.
DOI:	10.1126/scitranslmed.abc5332
Abstrakt:	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. (Copyright © 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).)
Databáze:	MEDLINE
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