Journal article
Identification and Biological Characterization of Heterocyclic Inhibitors of the Hepatitis C Virus RNA-dependent RNA Polymerase
The Journal of biological chemistry, v 277(41), pp 38322-38327
11 Oct 2002
PMID: 12167642
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The hepatitis C virus (HCV) NS5B protein encodes an RNA-dependent RNA polymerase (RdRp), the primary catalytic enzyme of the HCV replicase complex. We established a biochemical RNA synthesis assay, using purified recombinant NS5B lacking the C-terminal 21 amino acid residues, to identify potential polymerase inhibitors from a high throughput screen of the GlaxoSmithKline proprietary compound collection. The benzo-1,2,4-thiadiazine compound 1 was found to be a potent, highly specific inhibitor of NS5B. This agent interacts directly with the viral polymerase and inhibits RNA synthesis in a manner noncompetitive with respect to GTP. Furthermore, in the absence of anin vitro-reconstituted HCV replicase assay employing viral and host proteins, the ability of compound 1 to inhibit NS5B-directed viral RNA replication was determined using the Huh7 cell-based HCV replicon system. Compound 1 reduced viral RNA in replicon cells with an IC50 of ∼0.5 μm, suggesting that the inhibitor was able to access the perinuclear membrane and inhibit the polymerase activity in the context of a replicase complex. Preliminary structure-activity studies on compound 1 led to the identification of a modified inhibitor, compound 4, showing an improvement in both biochemical and cell-based potency. Lastly, data are presented suggesting that these compounds interfere with the formation of negative and positive strand progeny RNA by a similar mode of action. Investigations are ongoing to assess the potential utility of such agents in the treatment of chronic HCV disease.
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Details
- Title
- Identification and Biological Characterization of Heterocyclic Inhibitors of the Hepatitis C Virus RNA-dependent RNA Polymerase
- Creators
- Dashyant Dhanak - Cancer Genomics CentreKevin J. Duffy - Departments of Medicinal Chemistry and GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426Victor K. Johnston - Department of VirologyJuili Lin-Goerke - GlaxoSmithKlineMichael Darcy - Cancer Genomics CentreAntony N. Shaw - Departments of Medicinal Chemistry and GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426Baohua Gu - GlaxoSmithKlineCarol Silverman - GlaxoSmithKlineAdam T. Gates - GlaxoSmithKlineMichael R. Nonnemacher - GlaxoSmithKlineDavid L. Earnshaw - Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426David J. Casper - Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426Arun Kaura - Cancer Genomics CentreAudrey Baker - Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426Cathy Greenwood - Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426Lester L. Gutshall - GlaxoSmithKlineDerrick Maley - GlaxoSmithKlineAlfred DelVecchio - GlaxoSmithKlineRicardo Macarron - Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426Glenn A. Hofmann - Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426Zaid Alnoah - Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426Hung-Yuan Cheng - Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426George Chan - Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426Sanjay Khandekar - Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426Richard M. Keenan - Cancer Genomics CentreRobert T. Sarisky - GlaxoSmithKline
- Publication Details
- The Journal of biological chemistry, v 277(41), pp 38322-38327
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000178529600043
- Scopus ID
- 2-s2.0-0037064091
- Other Identifier
- 991020099164604721
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- Web of Science research areas
- Biochemistry & Molecular Biology