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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.
  • 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.
Sci Transl Med ; 12(557)2020 08 19.
Article in English | MEDLINE | ID: covidwho-694565
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pneumonia, Viral / Protease Inhibitors / Virus Replication / Viral Nonstructural Proteins / Coronavirus Infections / Middle East Respiratory Syndrome Coronavirus / Betacoronavirus Type of study: Prognostic study Language: English Journal subject: Science / Medicine Year: 2020 Document Type: Article Affiliation country: Scitranslmed.abc5332

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pneumonia, Viral / Protease Inhibitors / Virus Replication / Viral Nonstructural Proteins / Coronavirus Infections / Middle East Respiratory Syndrome Coronavirus / Betacoronavirus Type of study: Prognostic study Language: English Journal subject: Science / Medicine Year: 2020 Document Type: Article Affiliation country: Scitranslmed.abc5332