Discovery and Characterization of Substituted Diphenyl Heterocyclic Compounds as Potent and Selective Inhibitors of Hepatitis C Virus Replication

@article{citeulike:2604974, abstract = {A novel small-molecule inhibitor, referred to here as R706, was discovered in a high-throughput screen of chemical libraries against Huh-7-derived replicon cells carrying autonomously replicating subgenomic RNA of hepatitis C virus (HCV). R706 was highly potent in blocking HCV RNA replication as measured by real-time reverse transcription-PCR and Western blotting of R706-treated replicon cells. Structure-activity iterations of the R706 series yielded a lead compound, R803, that was more potent and highly specific for HCV replication, with no significant inhibitory activity against a panel of HCV-related positive-stranded RNA viruses. Furthermore, HCV genotype 1 replicons displayed markedly higher sensitivity to R803 treatment than a genotype 2a-derived replicon. In addition, R803 was tested by a panel of biochemical and cell-based assays for on-target and off-target activities, and the data suggested that the compound had a therapeutic window close to 100-fold, while its exact mechanism of action remained elusive. We found that R803 was more effective than alpha interferon (IFN-{alpha}) at blocking HCV RNA replication in the replicon model. In combination studies, R803 showed a weak synergistic effect with IFN-{alpha}/ribavirin but only additive effects with a protease inhibitor and an allosteric inhibitor of RNA-dependent RNA polymerase (20). We conclude that R803 and related heterocyclic compounds constitute a new class of HCV-specific inhibitors that could potentially be developed as a treatment for HCV infection. 10.1128/AAC.00525-07}, author = {Huang, Peiyong and Goff, Dane A. and Huang, Qi and Martinez, Anthony and Xu, Xiang and Crowder, Scott and Issakani, Sarkiz D. and Anderson, Emily and Sheng, Ning and Achacoso, Philip and Yen, Ann and Kinsella, Todd and Darwish, Ihab S. and Kolluri, Rao and Hong, Hui and Qu, Kunbin and Stauffer, Emily and Goldstein, Eileen and Singh, Rajinder and Payan, Donald G. and Lu, Henry H. }, citeulike-article-id = {2604974}, doi = {10.1128/AAC.00525-07}, journal = {Antimicrob. Agents Chemother.}, month = {April}, number = {4}, pages = {1419--1429}, posted-at = {2008-03-28 04:57:24}, priority = {2}, title = {Discovery and Characterization of Substituted Diphenyl Heterocyclic Compounds as Potent and Selective Inhibitors of Hepatitis C Virus Replication}, url = {http://dx.doi.org/10.1128/AAC.00525-07}, volume = {52}, year = {2008} }

TY - JOUR ID - citeulike:2604974 L3 - citeulike-article-id:2604974 TI - Discovery and Characterization of Substituted Diphenyl Heterocyclic Compounds as Potent and Selective Inhibitors of Hepatitis C Virus Replication JF - Antimicrob. Agents Chemother. VL - 52 IS - 4 SP - 1419 EP - 1429 N2 - A novel small-molecule inhibitor, referred to here as R706, was discovered in a high-throughput screen of chemical libraries against Huh-7-derived replicon cells carrying autonomously replicating subgenomic RNA of hepatitis C virus (HCV). R706 was highly potent in blocking HCV RNA replication as measured by real-time reverse transcription-PCR and Western blotting of R706-treated replicon cells. Structure-activity iterations of the R706 series yielded a lead compound, R803, that was more potent and highly specific for HCV replication, with no significant inhibitory activity against a panel of HCV-related positive-stranded RNA viruses. Furthermore, HCV genotype 1 replicons displayed markedly higher sensitivity to R803 treatment than a genotype 2a-derived replicon. In addition, R803 was tested by a panel of biochemical and cell-based assays for on-target and off-target activities, and the data suggested that the compound had a therapeutic window close to 100-fold, while its exact mechanism of action remained elusive. We found that R803 was more effective than alpha interferon (IFN-{alpha}) at blocking HCV RNA replication in the replicon model. In combination studies, R803 showed a weak synergistic effect with IFN-{alpha}/ribavirin but only additive effects with a protease inhibitor and an allosteric inhibitor of RNA-dependent RNA polymerase (20). We conclude that R803 and related heterocyclic compounds constitute a new class of HCV-specific inhibitors that could potentially be developed as a treatment for HCV infection. 10.1128/AAC.00525-07 AU - Huang, Peiyong AU - Goff, Dane AU - Huang, Qi AU - Martinez, Anthony AU - Xu, Xiang AU - Crowder, Scott AU - Issakani, Sarkiz AU - Anderson, Emily AU - Sheng, Ning AU - Achacoso, Philip AU - Yen, Ann AU - Kinsella, Todd AU - Darwish, Ihab AU - Kolluri, Rao AU - Hong, Hui AU - Qu, Kunbin AU - Stauffer, Emily AU - Goldstein, Eileen AU - Singh, Rajinder AU - Payan, Donald AU - Lu, Henry PY - 2008/04/01/ UR - http://dx.doi.org/10.1128/AAC.00525-07 ER -