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2 results on '"Yen KJ"'

1. Discovery of M Protease Inhibitors Encoded by SARS-CoV-2.

Author

Hung HC, Ke YY, Huang SY, Huang PN, Kung YA, Chang TY, Yen KJ, Peng TT, Chang SE, Huang CT, Tsai YR, Wu SH, Lee SJ, Lin JH, Liu BS, Sung WC, Shih SR, Chen CT, and Hsu JT

Subjects
Amino Acid Motifs, Animals, Antiviral Agents pharmacology, Betacoronavirus pathogenicity, Catalytic Domain, Chlorocebus aethiops, Coronavirus 3C Proteases, Cysteine Endopeptidases genetics, Cysteine Endopeptidases metabolism, Gene Expression, Molecular Docking Simulation, Protease Inhibitors pharmacology, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Pyrrolidines pharmacology, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, SARS-CoV-2, Sulfonic Acids, Thermodynamics, Vero Cells, Viral Nonstructural Proteins antagonists & inhibitors, Viral Nonstructural Proteins genetics, Viral Nonstructural Proteins metabolism, Virus Replication drug effects, Antiviral Agents chemistry, Betacoronavirus drug effects, Cysteine Endopeptidases chemistry, Protease Inhibitors chemistry, Pyrrolidines chemistry, Viral Nonstructural Proteins chemistry
Abstract

The coronavirus (CoV) disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is a health threat worldwide. Viral main protease (M pro , also called 3C-like protease [3CL pro ]) is a therapeutic target for drug discovery. Herein, we report that GC376, a broad-spectrum inhibitor targeting M pro in the picornavirus-like supercluster, is a potent inhibitor for the M pro encoded by SARS-CoV-2, with a half-maximum inhibitory concentration (IC 50 ) of 26.4 ± 1.1 nM. In this study, we also show that GC376 inhibits SARS-CoV-2 replication with a half-maximum effective concentration (EC 50 ) of 0.91 ± 0.03 μM. Only a small portion of SARS-CoV-2 M pro was covalently modified in the excess of GC376 as evaluated by mass spectrometry analysis, indicating that improved inhibitors are needed. Subsequently, molecular docking analysis revealed that the recognition and binding groups of GC376 within the active site of SARS-CoV-2 M pro provide important new information for the optimization of GC376. Given that sufficient safety and efficacy data are available for GC376 as an investigational veterinary drug, expedited development of GC376, or its optimized analogues, for treatment of SARS-CoV-2 infection in human is recommended., (Copyright © 2020 Hung et al.)

Published
2020
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2. Inhibition of enterovirus 71 replication and the viral 3D polymerase by aurintricarboxylic acid.

Author

Hung HC, Chen TC, Fang MY, Yen KJ, Shih SR, Hsu JT, and Tseng CP

Subjects
Animals, COS Cells, Cell Line, Tumor, Chlorocebus aethiops, Cytopathogenic Effect, Viral, Humans, Vero Cells, Viral Plaque Assay, Antiviral Agents pharmacology, Aurintricarboxylic Acid pharmacology, Enterovirus A, Human drug effects, Enzyme Inhibitors pharmacology, RNA-Dependent RNA Polymerase antagonists & inhibitors, Viral Proteins antagonists & inhibitors, Virus Replication drug effects
Abstract

Objectives: Enterovirus 71 (EV71) causes serious diseases in humans. The aim of this study was to examine the effects of aurintricarboxylic acid (ATA) on EV71 replication and to explore the underlying mechanism., Methods: To measure the activity of ATA in inhibiting the cytopathic effect (CPE) of EV71, a cell-based neutralization (inhibition of virus-induced CPE) assay was performed. The effect of ATA was further confirmed using plaque reduction and viral yield reduction assays. A time of addition assay was performed to identify the mechanisms of ATA's anti-EV71 activity. We examined the effects of ATA on the following key steps involved in virus replication: (i) translation of the internal ribosomal entry site (IRES)-mediated viral polyprotein; (ii) the proteolytic activity of viral proteases 2A and/or 3C; and (iii) the viral 3D RNA-dependent RNA polymerase (RdRp) activity., Results: In this study, ATA was found to be a potent inhibitor of the replication of EV71. In the antiviral neutralization assay, ATA exhibited inhibitory activity against EV71 (TW/4643/98) and EV71 (TW/2231/98). Plaque assay further demonstrated that ATA inhibited EV71 replication with an EC(50) (effective concentration at which 50% of plaques were removed) of 2.9 microM. Studies on the mechanism of action revealed that ATA targets the early stage of the viral life cycle after viral entry. ATA was able to inhibit the RdRp activity of EV71, while neither the IRES-mediated translation of viral polyprotein nor the viral 3C protease activity was affected., Conclusions: Overall, the findings in this study suggest that ATA is able to effectively inhibit EV71 replication through interfering with the viral 3D polymerase.

Published
2010
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