Optimization of Potent Hepatitis C Virus NS3 Helicase Inhibitors Isolated from the Yellow Dyes Thioflavine S Primuline
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Issue Date
2012-04-12Author
Li, Kelin
Frankowski, Kevin J.
Belon, Craig A.
Neuenswander, Benjamin
Ndjomou, Jean
Hanson, Alicia M.
Shanahan, Matthew A.
Schoenen, Frank J.
Blagg, Brian S. J.
Aubé, Jeffrey
Frick, David N.
Publisher
American Chemical Society
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm300021v.
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Show full item recordAbstract
A screen for hepatitis C virus (HCV) NS3 helicase inhibitors revealed that the commercial dye thioflavine S was the most potent inhibitor of NS3-catalyzed DNA and RNA unwinding in the 827-compound National Cancer Institute Mechanistic Set. Thioflavine S and the related dye primuline were separated here into their pure components, all of which were oligomers of substituted benzothiazoles. The most potent compound (P4), a benzothiazole tetramer, inhibited unwinding >50% at 2±1 μM, inhibited the subgenomic HCV replicon at 10 μM, and was not toxic at 100 μM. Because P4 also interacted with DNA, more specific analogs were synthesized from the abundant dimeric component of primuline. Some of the 29 analogs prepared retained ability to inhibit HCV helicase but did not appear to interact with DNA. The most potent of these specific helicase inhibitors (compound 17) was active against the replicon and inhibited the helicase more than 50% at 2.6±1 μM.
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Citation
Li, K., Frankowski, K. J., Belon, C. A., Neuenswander, B., Ndjomou, J., Hanson, A. M., … Frick, D. N. (2012). Optimization of Potent Hepatitis C Virus NS3 Helicase Inhibitors Isolated from the Yellow Dyes Thioflavine S and Primuline. Journal of Medicinal Chemistry, 55(7), 3319–3330. http://doi.org/10.1021/jm300021v
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