[6] Valopicitabine (Nm283), Alone or With Peg-Interferon, Compared to Peg Interferon/Ribavirin (Pegifn/Rbv) Retreatment in Patients With HCV-1 Infection and Prior Non-Response to Pegifn/Rbv: One-Year Results

Afdhal, Nezam H.; O’Brien, Christopher B.; Godofsky, Eliot; Rodrı́guez-Torres, Maribel; Pappas, S. Chris; Läwitz, E.; Pockros, Paul J.; Sulkowski, Mark S.; Jacobson, Ira M.; Gao, Chao; Knox, Steven J.; Pietropaolo, Keith; Brown, Nathaniel

doi:10.1016/s0168-8278(07)61604-3

Cited by 38 publications

(25 citation statements)

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“…Valopicitabine, the 3=-valyl ester oral prodrug of 2CMC, was shown to markedly reduce viral loads in chronically HCV-infected patients (24,25); however, its development was halted because of adverse effects. 2CMC, through its 5=-triphosphate metabolite, targets the active site of the viral RNA-dependent RNA polymerases (18,26).…”

Section: Discussionmentioning

confidence: 99%

The Viral Polymerase Inhibitor 2′- C -Methylcytidine Inhibits Norwalk Virus Replication and Protects against Norovirus-Induced Diarrhea and Mortality in a Mouse Model

Rocha‐Pereira

Jochmans

Debing

et al. 2013

J Virol

107

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Human noroviruses are a major cause of food-borne illness, accountable for 50% of all-etiologies outbreaks of acute gastroenteritis (in both developing and developed countries). There is no vaccine or antiviral drug for the prophylaxis or treatment of norovirus-induced gastroenteritis. We recently reported the inhibitory effect of 2=-C-methylcytidine (2CMC), a hepatitis C virus polymerase inhibitor, on the in vitro replication of murine norovirus (MNV). Here we evaluated the inhibitory effect of 2CMC on in vitro human norovirus replication through a Norwalk virus replicon model and in a mouse model by using AG129 mice orally infected with MNV. Survival, weight, and fecal consistency were monitored, and viral loads in stool samples and organs were quantified. Intestines were examined histologically. 2CMC reduced Norwalk virus replicon replication in a dose-dependent manner and was able to clear cells of the replicon. Treatment of MNV-infected AG129 mice with 2CMC (i) prevented norovirusinduced diarrhea; (ii) markedly delayed the appearance of viral RNA and reduced viral RNA titers in the intestine, mesenteric lymph nodes, spleen, lungs, and stool; (iii) completely prevented virus-induced mortality; and (iv) resulted in protective immunity against a rechallenge. We demonstrate for the first time that a small-molecule inhibitor of norovirus replication protects from virus-induced disease and mortality in a relevant animal model. These findings pave the way for the development of potent and safe antivirals as prophylaxis and therapy of norovirus infection.

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Section: Discussionmentioning

confidence: 99%

The Viral Polymerase Inhibitor 2′- C -Methylcytidine Inhibits Norwalk Virus Replication and Protects against Norovirus-Induced Diarrhea and Mortality in a Mouse Model

Rocha‐Pereira

Jochmans

Debing

et al. 2013

J Virol

107

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“…Valopicitabine (2Ј-C-methylcytidine [2Ј-CMC]) was the first nucleoside analogue to enter clinical trials. Development has been discontinued because of modest antiviral efficacy along with significant gastrointestinal side effects (2). RG7128, a prodrug of nucleoside analogue PSI-6130 (␤-D-2Ј-deoxy-2Ј-fluoro-2Ј-Cmethylcytidine), and PSI-7977, a liver-targeted prodrug of the uridine nucleotide analogue PSI-6206 monophosphate, are in phase II clinical trials.…”

mentioning

confidence: 99%

Comparative Study of the Genetic Barriers and Pathways towards Resistance of Selective Inhibitors of Hepatitis C Virus Replication

Delang

Vliegen

Froeyen

et al. 2011

Antimicrob Agents Chemother

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Hepatitis C virus (HCV) inhibitors include direct-acting antivirals (DAAs) such as NS3 serine protease inhibitors, nucleoside and nonnucleoside polymerase inhibitors, and host-targeting antivirals (HTAs) such as cyclophilin inhibitors that have been developed in recent years. Drug-resistant HCV variants have been reported both in vitro and in the clinical setting for most classes of drugs. We report a comparative study in which the genetic barrier to drug resistance of a representative selection of these inhibitors is evaluated employing a number of resistance selection protocols. The NS3 protease inhibitors VX-950 and BILN 2061, the nucleoside polymerase inhibitor 2-C-methylcytidine, three nonnucleoside polymerase inhibitors (thiophene carboxylic acid, benzimidazole, and benzothiadiazine), and DEB025 were included. For each drug and passage in the selection process, the phenotype and genotype of the drug-resistant replicon were determined. For a number of molecules (BILN 2061 and nonnucleoside inhibitors), drug-resistant variants were readily selected when wild-type replicon-containing cells were directly cultured in the presence of high concentrations of the inhibitor. Resistance to DEB025 could be selected only following a lengthy stepwise selection procedure. For some DAAs, the signature mutations that emerged under inhibitor pressure differed depending on the selection protocol that was employed. Replication fitness of resistant mutants revealed that the C445F mutation in the RNA-dependent RNA polymerase can restore loss of fitness caused by a number of unfit resistance mutations. These data provide important insights into the various pathways leading to drug resistance and allow a direct comparison of the genetic barriers of various HCV drugs.Hepatitis C virus (HCV) is a positive single-stranded RNA virus and the only member of the Hepacivirus genus within the Flaviviridae family. An estimated 170 million people are chronically infected worldwide. Three million to four million people become newly infected each year (57). Chronically infected patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. In Western countries, infection with HCV is the most common reason for liver transplantation. The current standard of care for the management of chronic hepatitis C virus infection consists of the combination of pegylated alpha interferon (pegIFN-␣) and ribavirin. This therapy is effective in only 50 to 60% of infected patients and is associated with serious side effects (44). Therefore, more tolerable, highly potent inhibitors of HCV replication are urgently needed and are currently also being developed. Antivirals that specifically target viral proteins are referred to as "direct-acting antivirals" (DAAs) for HCV. A number of NS3/NS4A protease inhibitors are currently in clinical development. The first HCV NS3/4A serine protease inhibitor to enter clinical trials was ciluprevir (BILN 2061) (54), but clinical development was halted because of cardiotoxicity. Other protease inhib...

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“…NM283 has demonstrated antiviral efficacy upon oral administration in HCV-infected patients (1,2,14,20). However, gastrointestinal side effects have limited the dose levels and resulted in the discontinuation of development of the compound.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2′- C -Methylcytidine to Hepatitis C Virus-Infected Chimpanzees

Carroll

Koeplinger

Vavrek

et al. 2011

Antimicrob Agents Chemother

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. One approach to increase the antiviral efficacy of 2-C-methylcytidine is to increase the concentration of the active inhibitory species, the 5-triphosphate, in infected hepatocytes. HepDirect prodrug technology can increase intracellular concentrations of a nucleoside triphosphate in hepatocytes by introducing the nucleoside monophosphate into the cell, bypassing the initial kinase step that is often rate limiting. Screening for 2-C-methylcytidine triphosphate levels in rat liver after oral dosing identified 1-[3,5-difluorophenyl]-1,3-propandiol as an efficient prodrug modification. To determine antiviral efficacy in vivo, the prodrug was administered separately via oral and intravenous dosing to two HCV-infected chimpanzees. Circulating viral loads declined by ϳ1.4 log 10 IU/ml and by >3.6 log 10 IU/ml after oral and intravenous dosing, respectively. The viral loads rebounded after the end of dosing to predose levels. The results indicate that a robust antiviral response can be achieved upon administration of the prodrug.Chronic hepatitis C virus (HCV) infection is associated with increased incidence of liver fibrosis, cirrhosis, and hepatocellular carcinoma and is the leading cause of liver transplantation in the United States (13). The current standard for treatment is a combination of pegylated interferon alpha and ribavirin, which results in sustained viral response (SVR) (undetectable virus 6 months after the end of treatment) in 50% or 80% of treated patients harboring a genotype 1 or a genotype 2 or 3 infection, respectively (25). Thus, novel therapies resulting in higher SVR rates, particularly in the treatment of genotype 1 infections, are needed.Nucleoside analogs inhibiting the HCV RNA polymerase have been investigated as potential therapeutics to treat HCV infections. 2Ј-C-Methylcytidine inhibits HCV RNA replication in the replicon assay (consensus 1 50% effective concentration [EC 50 ], ϳ1 M) via inhibition of the HCV RNA polymerase, which is inhibited by the 2Ј-C-methylcytidine triphosphate in vitro in cell-free biochemical assays (50% inhibitory concentration [IC 50 ], ϳ0.2 M) (15). NM283, the 3Ј-O-valinyl ester prodrug of 2Ј-C-methylcytidine, has improved oral bioavailability compared to 2Ј-C-methylcytidine (21) and has been investigated in HCV-infected patients in clinical studies. In a phase IIb study, patients receiving NM283 in combination with pegylated interferon alpha and ribavirin at 24 weeks of therapy experienced mean viral load reductions of up to 3.3 log 10 IU/ml compared to 2.3 log 10 IU/ml reductions for patients receiving pegylated interferon-ribavirin alone (2). Due to the high incidence of gastrointestinal side effects, which required reduction of the highest daily dose of 800 mg to 200 or 400 mg, further development of NM283 was placed on hold.The HepDirect prodrug modifications of nucleoside 5Ј-monophosphates (NMP) are substituted cyclic 1,3-propanyl esters that offer an opportunity to bypass the initial phosphorylation step that is often rate limiting for the formation of...

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[6] Valopicitabine (Nm283), Alone or With Peg-Interferon, Compared to Peg Interferon/Ribavirin (Pegifn/Rbv) Retreatment in Patients With HCV-1 Infection and Prior Non-Response to Pegifn/Rbv: One-Year Results

Cited by 38 publications

References 0 publications

The Viral Polymerase Inhibitor 2′- C -Methylcytidine Inhibits Norwalk Virus Replication and Protects against Norovirus-Induced Diarrhea and Mortality in a Mouse Model

The Viral Polymerase Inhibitor 2′- C -Methylcytidine Inhibits Norwalk Virus Replication and Protects against Norovirus-Induced Diarrhea and Mortality in a Mouse Model

Comparative Study of the Genetic Barriers and Pathways towards Resistance of Selective Inhibitors of Hepatitis C Virus Replication

Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2′- C -Methylcytidine to Hepatitis C Virus-Infected Chimpanzees

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