736 Early clearance of HCV RNA with valopicitabine (NM283) plus PEG-Interferon in treatment-naïve patients with HCV-1 infection: First results from a phase IIb trial

Dieterich, Doug; Läwitz, E.; Nguyen, Thanh Van; Younes, Ziad; Santoro, John J.; Gitlin, Norman; McEniry, D.; Chasen, Richard; Goff, John S.; Knox, Steven J.; Kleber, K.; Belanger, Bruce; Brown, NA

doi:10.1016/s0168-8278(06)80736-1

Cited by 26 publications

(19 citation statements)

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“…Both NS5B polymerase and NS3 protease have been the prime targets for the development of HCV-specific agents. To date, multiple small molecules against the two targets have been reported (7,17,18,48), and some of them have shown antiviral activity in HCV-infected patients (9,20,42,43,44,54).…”

mentioning

confidence: 99%

Selection of Replicon Variants Resistant to ACH-806, a Novel Hepatitis C Virus Inhibitor with No Cross-Resistance to NS3 Protease and NS5B Polymerase Inhibitors

Yang

Zhao

Fabrycki

et al. 2008

Antimicrob Agents Chemother

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We have discovered a novel class of compounds active against hepatitis C virus (HCV), using a surrogate cellular system, HCV replicon cells. The leading compound in the series, ACH-806 (GS-9132), is a potent and specific inhibitor of HCV. The selection of resistance replicon variants against ACH-806 was performed to map the mutations conferring resistance to ACH-806 and to determine cross-resistance profiles with other classes of HCV inhibitors. Several clones emerged after the addition of ACH-806 to HCV replicon cells at frequencies and durations similar to that observed with NS3 protease inhibitors and NS5B polymerase inhibitors. Phenotypic analyses of these clones revealed that they are resistant to ACH-806 but remain sensitive to other classes of HCV inhibitors. Moreover, no significant change in the susceptibility to ACH-806 was found when the replicon cellular clones resistant to NS3 protease inhibitors and NS5B polymerase inhibitors were examined. Sequencing of the entire coding region of ACH-806-resistant replicon variants yielded several consensus mutations. Reverse genetics identified two single mutations in NS3, a cysteine-to-serine mutation at amino acid 16 and an alanine-to-valine mutation at amino acid 39, that are responsible for the resistance of the replicon variants to ACH-806. Both mutations are located at the N terminus of NS3 where extensive interactions with the central hydrophobic region of NS4A exist. These data provide evidence that ACH-806 inhibits HCV replication by a novel mechanism.Hepatitis C virus (HCV) is the leading cause of liver disease worldwide. It is estimated that 170 million individuals are infected with HCV (56). The current therapeutic combination of pegylated alpha interferon (IFN-␣) and ribavirin has a sustained viral response rate of ϳ50% in genotype 1 HCV-infected patients and is limited by the adverse effects of both agents (8, 13). Therefore, the development of oral anti-HCV agents with improved efficacy and better tolerance is urgently needed.HCV is an enveloped virus with a positive-stranded RNA genome of 9.6 kb. The viral genome encodes a large polyprotein that is cleaved cotranslationally and/or posttranslationally into at least 10 mature viral proteins: C, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B (3, 26). Specific functions have been attributed to most of these viral proteins. For example, NS5B protein has an RNA-dependent RNA polymerase activity, the amino-terminal domain of NS3 carries serine protease activity, and NS4A is a cofactor of NS3 which enhances NS3 protease activity by forming a stable heterodimeric complex with NS3 (4,5,24,26,28,30). Both NS5B polymerase and NS3 protease have been the prime targets for the development of HCV-specific agents. To date, multiple small molecules against the two targets have been reported (7,17,18,48), and some of them have shown antiviral activity in HCV-infected patients (9,20,42,43,44,54).Among HCV-specific inhibitors discovered so far, NS5B nucleoside analogs target the polymerase catalytic site of NS5B. T...

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mentioning

confidence: 99%

Selection of Replicon Variants Resistant to ACH-806, a Novel Hepatitis C Virus Inhibitor with No Cross-Resistance to NS3 Protease and NS5B Polymerase Inhibitors

Yang

Zhao

Fabrycki

et al. 2008

Antimicrob Agents Chemother

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“…62,68 , Valopicitabine, [69][70][71][72] R-1479 and its prodrug Balapiravir R-1626 [73][74][75][76][77][78][79] as shown in Figure 9.…”

Section: Idx184mentioning

confidence: 99%

Antiviral Nucleoside and Nucleotide Analogs: A Review

Mahmoud

Hasabelnaby

Hammad

et al. 2018

Journal of Advanced Pharmacy Research

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Virus infections are an increasing and probably lasting global risk. Nucleoside and nucleotide analogs represent the largest class of antiviral drugs. Early success in the treatment of human immunodeficiency virus infection and the recent approval of sofosbuvir as phosphoramidate nucleoside prodrug for chronic hepatitis C have provided proof of concept for important this class of compounds as an antiviral agent. This review summarizes the antiviral activity of nucleoside and nucleotide analogs and their recent application.

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“…In a Phase IIb clinical trial, a 48 weeks combination of valopicitabine and IFN was evaluated in treatment-naïve subjects with HCV GT1 (Dieterich et al, 2006; Lawitz et al, 2007). This study was divided into five treatment groups: (A) IFN alone (180 μg QW = once weekly) for 4 weeks, valopicitabine 800 mg/day starting at week 5; (B) valopicitabine 200 mg/day + IFN (180 μg QW); (C–E) valopicitabine 800 mg/day with various week 1 induction regimens + IFN (180 μg QW).…”

Section: Valopicitabine (Nm283): the First Clinical Hcv Nucleosidementioning

confidence: 99%

Chutes and ladders in hepatitis C nucleoside drug development

et al. 2014

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Chutes and Ladders is an exciting up-and-down-again game in which players race to be the first to the top of the board. Along the way, they will find ladders to help them advance, and chutes that will cause them to move backwards. The development of nucleoside analogs for clinical treatment of hepatitis C presents a similar scenario in which taking shortcuts may help quickly advance a program, but there is always a tremendous risk of being sent backwards as one competes for the finish line. In recent years the treatment options for chronic hepatitis C virus (HCV) infection have expand due to the development of a replicon based in vitro evaluation system, allowing for the identification of multiple drugable viral targets along with a concerted and substantial drug discovery effort. Three major drug targets have reached clinical study for chronic HCV infection: the NS3/4A serine protease, the large phosphoprotein NS5A, and the NS5B RNA-dependent RNA polymerase. Recently, two oral HCV protease inhibitors were approved by the FDA and were the first direct acting anti-HCV agents to result from the substantial research in this area. There are currently many new chemical entities from several different target classes that are being evaluated worldwide in clinical trials for their effectiveness at achieving a sustained virologic response (SVR) (Pham et al., 2004; Radkowski et al., 2005). Clearly the goal is to develop therapies leading to a cure that are safe, widely accessible and available, and effective against all HCV genotypes (GT), and all stages of the disease. Nucleoside analogs that target the HCV NS5B polymerase that have reached human clinical trials is the focus of this review as they have demonstrated significant advantages in the clinic with broader activity against the various HCV GT and a higher barrier to the development of resistant viruses when compared to all other classes of HCV inhibitors.

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736 Early clearance of HCV RNA with valopicitabine (NM283) plus PEG-Interferon in treatment-naïve patients with HCV-1 infection: First results from a phase IIb trial

Cited by 26 publications

References 0 publications

Selection of Replicon Variants Resistant to ACH-806, a Novel Hepatitis C Virus Inhibitor with No Cross-Resistance to NS3 Protease and NS5B Polymerase Inhibitors

Selection of Replicon Variants Resistant to ACH-806, a Novel Hepatitis C Virus Inhibitor with No Cross-Resistance to NS3 Protease and NS5B Polymerase Inhibitors

Antiviral Nucleoside and Nucleotide Analogs: A Review

Chutes and ladders in hepatitis C nucleoside drug development

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