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    Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase

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    Sweeney_ACS_2015.pdf (557.4Kb)
    Issue Date
    2015-03-13
    Author
    Sweeney, Noreena L.
    Hanson, Alicia M.
    Mukherjee, Sourav
    Ndjomou, Jean
    Geiss, Brian J.
    Steel, J. Jordan
    Frankowski, Kevin J.
    Li, Kelin
    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
    The flavivirus nonstructural protein 3 (NS3) is a protease and helicase, and on the basis of its similarity to its homologue encoded by the hepatitis C virus (HCV), the flavivirus NS3 might be a promising drug target. Few flavivirus helicase inhibitors have been reported, in part, because few specific inhibitors have been identified when nucleic acid unwinding assays have been used to screen for helicase inhibitors. To explore the possibility that compounds inhibiting NS3-catalyzed ATP hydrolysis might function as antivirals even if they do not inhibit RNA unwinding in vitro, we designed a robust dengue virus (DENV) NS3 ATPase assay suitable for high-throughput screening. Members of two classes of inhibitory compounds were further tested in DENV helicase-catalyzed RNA unwinding assays, assays monitoring HCV helicase action, subgenomic DENV replicon assays, and cell viability assays and for their ability to inhibit West Nile virus (Kunjin subtype) replication in cells. The first class contained analogues of NIH molecular probe ML283, a benzothiazole oligomer derived from the dye primuline, and they also inhibited HCV helicase and DENV NS3-catalyzed RNA unwinding. The most intriguing ML283 analogue inhibited DENV NS3 with an IC50 value of 500 nM and was active against the DENV replicon. The second class contained specific DENV ATPase inhibitors that did not inhibit DENV RNA unwinding or reactions catalyzed by HCV helicase. Members of this class contained a 4-hydroxy-3-(5-methylfuran-2-carbonyl)-2H-pyrrol-5-one scaffold, and about 20 μM of the most potent pyrrolone inhibited both DENV replicons and West Nile virus replication in cells by 50%.
    URI
    http://hdl.handle.net/1808/23840
    DOI
    https://doi.org/10.1021/id5000458
    Collections
    • Chemistry Scholarly Works [610]
    Citation
    Sweeney, N. L., Hanson, A. M., Mukherjee, S., Ndjomou, J., Geiss, B. J., Steel, J. J., … Frick, D. N. (2015). Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase. ACS Infectious Diseases, 1(3), 140–148. http://doi.org/10.1021/id5000458

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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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