Hepatitis C virus

The hepatitis C virus (HCV) is at the origin of severe liver diseases. The current available treatment is based on a cytokine with low efficacy and many side effects. The NS5B protein plays a central role in the replication of HCV and is [Pg.372]

FIGURE 17.10 Epibatidine and analogs. The two conformers lA and IB were locked into two different scaffolds. Only syn-2 conserved some affinity in binding experiments. [Pg.373]

FIGURE 17.11 With a dihedral angle at 47°, compound 17 was the best Ugand in the series. The relative mentation of the indolyl part and the aryl [Pg.373]

CHAPTER 17 Conformational Restriction and/or Steric Hindrance in Medicinai Chemistry [Pg.374]

Hepatitis C, a contagious liver disease, results from infection with the hepatitis C virus (HCV). It can range in severity from a mild illness lasting a few weeks to a serious lifelong illness that damages the liver. Hepatitis C can occur in acute or chronic forms. Consider acute hepatitis C [Pg.199]

Note Employees who decline to accept the hepatitis B vaccination must sign a declination form indicating the employer offered the vaccination. [Pg.199]

Hepatitis C virus (HCV) Hepatocellular carcinoma 5 -untranslated/ cor region Inhibition of viral gene expression... [Pg.188]

Similar to HBV, infections with hepatitis C virus (HCV) have a high rate of progression from an acute to a chronic state that frequently leads to cirrhosis or hepatocellular carcinoma [2]. Monotherapy for HCV infection with IFN-a or combined therapy with ribavirin and IFN-a is associated with initial rates of response as high as 40%. The rates of sustained responses are, however, lower and also depend on the viral genotype. In patients infected with HCV genotype 2 or 3, the response was maximal after 24 weeks of treatment, whereas patients infected with genotype 1 -the most frequent in the USA and Europe - required a minimum treatment course of 48 weeks for an optimal outcome. [Pg.645]

The infectious cycle of a (+)-strand RNA virus such as the hepatitis C virus differs by the fate of the viral RNA genome in the infected cell. Upon entry into the cell, the HCV genome is used as a messenger RNA to drive the synthesis of a large polyprotein precursor of about 3,000 residues [2]. The structural proteins are excised from the precursor by host cell signal peptidase. [Pg.1285]

Thomson JA, Perni RB (2006) Hepatitis C virus NS3-4A protease inhibitors countering viral subversion in vitro and showing promise in the clinic. Curr Opin Drug Discov Devel 9 606-617... [Pg.1287]

These modified Rosenmund von Braun reaction conditions were also used by Gopalsamy et al. for the rapid cyanation of the 1,3,4,9-tetrahydropyrano-[3,4-fc]indole skeleton while searching for potent and selective Hepatitis C virus polymerase inhibitors (Scheme 74) [84]. [Pg.194]

Li XD, Sun L, Seth RB, Pineda G, Chen ZJ (2005) Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci USA 102 17717-17722... [Pg.23]

Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437 1167-1172... [Pg.23]

Approaches for the Development of Antiviral Compounds The Case of Hepatitis C Virus... [Pg.25]

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)... [Pg.47]

Di Marco S, Volpari C, Tomei L, Altamura S, Harper S, Narjes F, Koch U, Rowley M, De Francesco R, Mighaccio G, Card A (2005) Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site. J Biol Chem 280 29765-29770... [Pg.47]

Dutartre H, Bussetta C, Boretto J, Canard B (2006) General catalytic deficiency of hepatitis C virus RNA polymerase with an S282T mutation and mutually exclusive resistance towards 2 -modified nucleotide analogues. Antimicrob Agents Chemother 50 4161 169 Elferink RO, Groen AK (2002) Genetic defects in hepatobiliary transport. Biochim Biophys Acta... [Pg.47]

NMR structural characterization of peptide inhibitors bound to the Hepatitis C virus NS3 protease design of a new P2 substituent. J Med Chem 47 123-132... [Pg.47]

Koch U, Naqes F (2006) Allosteric inhibition of the hepatitis C virus NS5B RNA dependent RNA polymerase. Infect Disord Drug Targets 6 31 1... [Pg.48]

Lesburg CA, Cable MB, Ferrari E, Hong Z, Mannarino AF, Weber PC (1999) Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site, Nat Struct Biol 6 937-943... [Pg.48]

Lin C, Lin K, Luong YP, Rao BG, Wei YY, Brennan DL, Fulghum JR, Hsiao HM, Ma S, Maxwell JP, Cottrell KM, Pemi RB, Gates CA, Kwong AD (2004) In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061 structural analysis indicates different resistance mechanisms. J Biol Chem 279 17508-17514... [Pg.49]

Ranjith-Kumar CT, Kim YC, Gutshall L, Silverman C, Khandekar S, Sarisky RT, Kao CC (2002) Mechanism of de novo initiation by the hepatitis C virus RNA-dependent RNA polymerase role of divalent metals, J Virol 76 12513-12525... [Pg.50]

Shepard CW, Finelli L, Alter MJ (2005) Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 5 558-567... [Pg.50]

Stuyver LJ, McBrayer TR, Tharnish PM, Hassan AE, Chu CK, Pankiewicz KW, Watanabe KA, Schinazi RF, Otto MJ (2003a) Dynamics of subgenomic hepatitis C virus replicon RNA levels in Huh-7 cells after exposure to nucleoside antimetabohtes, J Virol 77 10689-10694... [Pg.50]

Stuyver LJ, Whitaker T, McBrayer TR, Hernandez-Santiago BI, Lostia S, Tharnish PM, Ramesh M, Chu CK, Jordan R, Shi J, Rachakonda S, Watanabe KA, Otto MJ, Schinazi RF (2003b) Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses in culture, Antimicrob Agents Chemother 47 244-254... [Pg.50]

Stuyver LJ, McBrayer TR, Tharnish PM, Clark J, Hollecker L, Lostia S, Nachman T, Grier J, Bennett MA, Xie MY, Schinazi RF, Morrey JD, Inlander JL, Furman PA, Otto MJ (2006a) Inhibition of hepatitis C replicon RNA synthesis by beta-D-2 -deoxy-2 -fluoro-2 -C-methylcytidine a specific inhibitor of hepatitis C virus replication, Antivir Chem Chemother 17 79-87... [Pg.50]

Tai CL, Chi WK, Chen DS, Hwang LH (1996) The helicase activity associated with hepatitis C virus nonstructural protein 3 (NS3). J Virol 70 8477-8484 Tong X, Chase R, Skelton A, Chen T, Wright-Minogue J, Malcolm BA (2006) Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Antiviral Res 70 28-38... [Pg.52]

Zhong W, Uss AS, Ferrari E, Lau JY, Hong Z (2000) De novo initiation of RNA synthesis by hepatitis C virus nonstructural protein 5B polymerase. J Virol 74 2017-2022 Zhou S, Yung Chan S, Cher Goh B, Chan E, Duan W, Huang M, McLeod HL (2005) Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharma-cokinet 44 279-304... [Pg.52]

C-methyl group or 4 -C-azido group in nucleoside analogues targeting the hepatitis C virus (HCV) RNA polymerase NS5B. [Pg.55]

Nucleoside inhibitors of hepatitis C virus RNA polymerase improved potency and liver targeting with 7-deaza-7-fluoro-2 -C-methyladenosine. In Late breaker presentations. 20th international conference on antiviral research, Palm Springs, CA, USA, April 29-May 3, 2007, LB-01... [Pg.80]

Coelmont L, Paeshuyse J, Windisch MP, De Clercq E, Bartenschlager R, Neyts J (2006) Ribavirin antagonizes the in vitro anti-hepatitis C virus activity of 2 -C-methylcytidine, the active component of valopicitabine. Antimicrob Agents Chemother 50 3444-3446 D Abramo CM, Cellai L, GOtte M (2004) Excision of incorporated nucleotide analogue chain-terminators can diminish their inhibitory effects on viral RNA-dependent RNA polymerases. J Mol Biol 337 1-14... [Pg.80]

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... [Pg.81]

Ludmerer SW, Graham DJ, Boots E, Murray EM, Simcoe A, Markel EJ, Grobler JA, Flores OA, Olsen DB, Hazuda DJ, LaFemina RL (2005) Replication fitness and NS5B drug sensitivity of diverse hepatitis C virus isolates characterized by using a transient replication assay. Antimicrob Agents Chemother 49 2059-2069... [Pg.82]

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