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    Simultaneously Targeting the NS3 Protease And Helicase Activities For More Effective Hepatitis C Virus Therapy

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    Ndjomou_ACS_2015.pdf (581.8Kb)
    Issue Date
    2015-08-21
    Author
    Ndjomou, Jean
    Corby, M. Josie
    Sweeney, Noreena L.
    Hanson, Alicia M.
    Aydin, Cihan
    Ali, Akbar
    Schiffer, Celia A.
    Li, Kelin
    Frankowski, Kevin J.
    Schoenen, Frank J.
    Frick, David N.
    Publisher
    ACS
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    Copyright © 2015 American Chemical Society
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    Abstract
    This study examines the specificity and mechanism of action of a recently reported hepatitis C virus (HCV) non-structural protein 3 (NS3) helicase-protease inhibitor (HPI), and the interaction of HPI with the NS3 protease inhibitors telaprevir, boceprevir, danoprevir, and grazoprevir. HPI most effectively reduced cellular levels of subgenomic genotype 4a replicons, followed by genotypes 3a and 1b replicons. HPI had no effect on HCV genotype 2a or dengue virus replicon levels. Resistance evolved more slowly to HPI than telaprevir, and HPI inhibited telaprevir-resistant replicons. Molecular modeling and analysis of the ability of HPI to inhibit peptide hydrolysis catalyzed by a variety of wildtype and mutant NS3 proteins suggested that HPI forms a bridge between the NS3 RNA-binding cleft and an allosteric site previously shown to bind other protease inhibitors. In most combinations, the antiviral effect of HPI was additive with telaprevir, boceprevir, minor synergy was observed with danoprevir and modest synergy was observed with grazoprevir.
    URI
    http://hdl.handle.net/1808/23828
    DOI
    https://doi.org/10.1021/acschembio.5b00101
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Ndjomou, J., Corby, M. J., Sweeney, N. L., Hanson, A. M., Aydin, C., Ali, A., … Frick, D. N. (2015). Simultaneously Targeting the NS3 Protease And Helicase Activities For More Effective Hepatitis C Virus Therapy. ACS Chemical Biology, 10(8), 1887–1896. http://doi.org/10.1021/acschembio.5b00101

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    KU Libraries
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    785-864-8983

    KU Libraries
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    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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