Hepatitis C virus NS5B polymerase

Deval J, D Abramo CM, GOtte M (2006) Selective excision of non-obUgate chain-terminators by the hepatitis C virus NS5B polymerase. In 16th international HIV Drug Resistance workshop, Sitges, Spain, June 13-17, 2006. Antivir Ther 11 Suppl 1 S3 (abstract no 1)... 

Deval J, Powdrill MH, D Abramo CM, Cellai L, Gotte M (2007) Pyrophosphorolytic excision of nonobligate chain terminators by hepatitis C virus NS5B polymerase. Antimicrob Agents Chemother 51 2920-2928... 

Kukolj G, McGibbon GA, McKercher G, Marquis M, Lefebvre S, Thauvette L, Gauthier J, Goulet S, Poupait MA, Beaulieu PL (2005) Binding site characterization and resistance to a class of non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase, J Biol Chem 280 39260-39267... 

Ishidaa, T., Suzuki, T., Hirashimaa, S., Mizutani, K., Yoshida, A., Ando, I., Ikeda, S., Adachi, T., Hashimoto, H. Benzimidazole inhibitors of hepatitis C virus NS5B polymerase identification of 2-[(4-diarylmethoxy)phenyl]-benzimidazole. Bioorg. Med. Chem. Lett. 2006, 36, 1859-1863. 

Biswal, . K., Wang, M., Cherney, M. M., Chan, L., Yannopoulos, C. G., Bilimoria, D., Bedard, J., James, M. N. (2006) Nonnucleoside inhibitors binding to hepatitis C virus NS5B polymerase reveal a novel mechanism of inhibition. /Mol Biol 361, 33-45. 

Isothiazoles have been incorporated into selective ChK2 (checkpoint kinase 2) inhibitor 212 <07BMCL172> and HCV (hepatitis C virus) NS5B polymerase inhibitor 213 <07BMCL28>, sultam into CDK (cyclin-dependent kinase) inhibitor 214 <07BMCL1284>, and trioxo-benzoisothiazole into the non-hepatotoxic acetaminophen analog 215 <07BMC2206>. 

Koch U, Naqes F (2006) Allosteric inhibition of the hepatitis C virus NS5B RNA dependent RNA polymerase. Infect Disord Drug Targets 6 31 1... 

Ikegashira et al. reported another recent example of the successful exploitation of conformational locks. They describe the discovery of a novel class of hepatitis C virus NS5B RNA polymerase inhibitors [42]. By designing and synthesizing conformationally constrained analogs of 40 (see Fig. 8.9), they obtained a series of novel compounds with significantly improved potency. Compound 41 was, for example, shown to be 7-fold more potent, see Fig. 8.9. 

C-methyl group or 4 -C-azido group in nucleoside analogues targeting the hepatitis C virus (HCV) RNA polymerase NS5B. 

Darke PL, Cole JL, Waxman L, Hall DL, Sardana MK, Kuo LC (1996) Active human cytomegalovirus protease is a dimer. J Biol Chem 271 7445-7449 De Francesco R, Carfi A (2007) Advances in the development of new therapeutic agents targeting the NS3 A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus. Adv Drug Deliv Rev 59 1242-1262... 

Currently, there is no approved antiviral therapy specifically targeting hepatitis C virus (HCV). The development of an HCV replicon system and our improved understanding of the structure and function of HCV proteins have led to the development of several classes of specific HCV inhibitors. NS3-4A protease inhibitors and NS5B polymerase inhibitors are furthest in development as discussed in Chaps. 2-4 (De and Migliaccio 2005 Manns et al. 2007 Pawlotsky et al. 2007). 

Maag D, Castro C, Hong Z, et al. Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. J Biol Chem 2001 276 46094-8. 

Several examples of this widely practiced name reaction have been applied in drug discovery abound. For example in a study describing the design and synthesis of inhibitors of hepatitis C virus (HCV) NS5B polymerase, thiazole intermediate was constructed via the Gabriel reaction, ... 

Returning attention to macrolactamization, a variation on the traditional amine-acid coupling was employed to access a series of finger loop inhibitors of hepatitis C virus (HCV) nonstructural protein 5B (NS5b) polymerase leading to the discovery of the clinical candidate TMC647055 (13, Scheme 11.2, GDI... 

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