Discovery and characterization of substituted diphenyl heterocyclic compounds as potent and selective inhibitors of hepatitis C virus replication.
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.
Huang
Peiyong
P
Department of Virology, Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
Goff
Dane A
DA
Huang
Qi
Q
Martinez
Anthony
A
Xu
Xiang
X
Crowder
Scott
S
Issakani
Sarkiz D
SD
Anderson
Emily
E
Sheng
Ning
N
Achacoso
Philip
P
Yen
Ann
A
Kinsella
Todd
T
Darwish
Ihab S
IS
Kolluri
Rao
R
Hong
Hui
H
Qu
Kunbin
K
Stauffer
Emily
E
Goldstein
Eileen
E
Singh
Rajinder
R
Payan
Donald G
DG
Lu
H Henry
HH
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D024882:Drug Resistance, Viral; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008826:Microbial Sensitivity Tests / Q000379:methods*; D012367:RNA, Viral / Q000096:biosynthesis; D012093:Replicon / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D001572:Benzofurans; D006571:Heterocyclic Compounds; D016898:Interferon-alpha; D012367:RNA, Viral; C010258:enprofen