title: Optimization of potent hepatitis C virus NS3 helicase inhibitors isolated from the yellow dyes thioflavine S and primuline.
abstract: 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 analogues were synthesized from the abundant dimeric component of primuline. Some of the 32 analogues 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.
authors.affiliation: University of Kansas Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA.
authors.forename: Kelin
authors.initials: K
authors.lastname: Li
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Frankowski
authors.forename: Craig A
authors.initials: CA
authors.lastname: Belon
authors.forename: Ben
authors.initials: B
authors.lastname: Neuenswander
authors.forename: Jean
authors.initials: J
authors.lastname: Ndjomou
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Hanson
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Shanahan
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Schoenen
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.forename: David N
authors.initials: DN
authors.lastname: Frick
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D052160:Benzothiazoles; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004396:Coloring Agents / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D051379:Mice; D011108:Polymers; D011485:Protein Binding; D020365:RNA Helicases / Q000037:antagonists & inhibitors*; D012367:RNA, Viral / Q000378:metabolism; D012093:Replicon; D012995:Solubility; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D052160:Benzothiazoles; D001798:Blood Proteins; D004396:Coloring Agents; D011108:Polymers; D020365:RNA Helicases; D012367:RNA, Viral; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C009462:thioflavin T; C035646:primuline