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Biotech / Medical : Indications -- Hepatitis -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (54)	12/10/2003 5:02:07 PM
From: tuck	Read Replies (1) \| Respond to of 312

[Inhibition of host protein geranylgeranylation as therapeutic strategy for HCV treatment] >>Published online before print December 10, 2003 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.2237238100 Medical Sciences Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation Jin Ye , Chunfu Wang , Rhea Sumpter Jr. , Michael S. Brown , Joseph L. Goldstein , and Michael Gale Jr. Departments of Molecular Genetics and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390 Contributed by Joseph L. Goldstein, November 6, 2003 Hepatitis C virus (HCV) RNA replication depends on viral protein association with intracellular membranes, but the influence of membrane composition on viral replication is unclear. We report that HCV RNA replication and assembly of the viral replication complex require geranylgeranylation of one or more host proteins. In cultured hepatoma cells, HCV RNA replication was disrupted by treatment with lovastatin, an inhibitor of 3-hydroxy-3-methyglutaryl CoA reductase, or with an inhibitor of protein geranylgeranyl transferase I, each of which induced the dissolution of the HCV replication complex. Viral replication was not affected by treatment of cells with an inhibitor of farnesyl transferase. When added to lovastatin-treated cells, geranylgeraniol, but not farnesol, restored replication complex assembly and viral replication. Inasmuch as the HCV genome does not encode a canonical geranylgeranylated protein, the data suggest the involvement of a geranylgeranylated host protein in HCV replication. Inhibition of its geranylgeranylation affords a therapeutic strategy for treatment of HCV infection.<< Cheers, Tuck

To: tuck who wrote (54)	8/2/2004 6:28:05 PM
From: tuck	Read Replies (1) \| Respond to of 312

[Benzimidazole 5-carboxylic amide derivatives -- Boehringer Ingelheim] Not content with BILN 2061, BI is working on this class. The following is a result of medicinal chemistry applied to the leads discovered in the full text freebie linked below (if memory serves, BI purchased Biochem Pharma of early HIV fame, and this effort is coming from there) . . . >>Bioorg Med Chem Lett. 2004 Feb 23;14(4):967-71. Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency. Beaulieu PL, Bos M, Bousquet Y, DeRoy P, Fazal G, Gauthier J, Gillard J, Goulet S, McKercher G, Poupart MA, Valois S, Kukolj G. Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5. pbeaulieu@lav.boehringer-ingelheim.com Optimization of benzimidazole 5-carboxamide derivatives previously identified as specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) has led to the discovery of potent analogues that inhibit the enzyme at low-nanomolar concentrations. Greater than 800-fold improvement in potency from the original lead structure was achieved through the combined effects of conformational rigidification, molecular size extension and the identification of previously unexploited interactions. Furthermore, these inhibitors retain specificity for HCV polymerase relative to other viral and mammalian RNA polymerases.<< nar.oupjournals.org Cheers, Tuck