Optimization of potent hepatitis C virus NS3 helicase inhibitors isolated from the yellow dyes thioflavine S and primuline.
Optimization of potent hepatitis C virus NS3 helicase inhibitors isolated from the yellow dyes thioflavine S and primuline.
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DOI：
10.1021/jm300021v
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发表时间：
2012-04-12
影响因子：
7.3
通讯作者：
Frick, David N.
中科院分区：
文献类型：
--
作者：
Li, Kelin;Frankowski, Kevin J.;Belon, Craig A.;Neuenswander, Ben;Ndjomou, Jean;Hanson, Alicia M.;Shanahan, Matthew A.;Schoenen, Frank J.;Blagg, Brian S. J.;Aube, Jeffrey;Frick, David N.
丙型肝炎病毒（HCV）NS3解旋酶抑制剂的筛选显示，商业染料硫代黄素S是827化合物国家癌症研究所机制组中NS3催化的DNA和RNA解旋的最有效抑制剂。硫代黄素S和相关染料樱草碱在这里被分离成它们的纯组分，它们都是取代苯并噻唑的低聚物。最有效的化合物（P4）是一种苯并噻唑四聚体，在2±1 μM时抑制解旋>50%，在10 μM时抑制亚基因组HCV复制子，在100 μM时无毒性。由于P4也与DNA相互作用，因此从樱草碱的丰富二聚体组分合成了更特异的类似物。制备的29种类似物中的一些保留了抑制HCV解旋酶的能力，但似乎不与DNA相互作用。这些特异性解旋酶抑制剂中最有效的（化合物17）对复制子具有活性，并在2.6±1 μM下抑制解旋酶超过50%。
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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DOI：
10.1038/nrd1853
发表时间：
2005-10
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Kwong AD;Rao BG;Jeang KT
通讯作者：
Jeang KT
影响因子：
2.7
作者：
Gemma, Sandra;Butini, Stefania;Maga, Giovanni
通讯作者：
Maga, Giovanni
影响因子：
15
作者：
Boger, DL;Fink, BE;Hedrick, MP
通讯作者：
Hedrick, MP
影响因子：
5.4
作者：
Kolykhalov, AA;Mihalik, K;Rice, CM
通讯作者：
Rice, CM
影响因子：
3.1
作者：
Belon CA;Frick DN
通讯作者：
Frick DN