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Discovery and characterization of substituted diphenyl heterocyclic compounds as potent and selective inhibitors of hepatitis C virus replication.

Huang, Peiyong; Goff, Dane A; Huang, Qi; Martinez, Anthony; Xu, Xiang; Crowder, Scott; Issakani, Sarkiz D; Anderson, Emily; Sheng, Ning; Achacoso, Philip; Yen, Ann; Kinsella, Todd; Darwish, Ihab S; Kolluri, Rao; Hong, Hui; Qu, Kunbin; Stauffer, Emily; Goldstein, Eileen; Singh, Rajinder; Payan, Donald G; Lu, H Henry.
Antimicrob Agents Chemother ; 52(4): 1419-29, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18227176
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.