Optimization of Potent
Hepatitis C Virus NS3 Helicase
Inhibitors Isolated from the Yellow Dyes Thioflavine S and Primuline
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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
(<b>P4</b>), 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 <b>P4</b> 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 <b>17</b>) was active against the replicon and inhibited
the helicase more than 50% at 2.6 ± 1 μM