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Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled,…
The Novel Nucleoside Analog R1479 (4′-Azidocytidine) Is a Potent Inhibitor of NS5B-dependent RNA Synthesis and Hepatitis C Virus Replication in Cell Culture*
Hepatitis C virus (HCV) polymerase activity is essential for HCV replication and the corresponding 5′-triphosphate derivative (R1479-TP) is a potent inhibitor of native HCV replicase isolated from replicon cells and of recombinant HCV polymerase (NS5B)-mediated RNA synthesis activity.
The Hepatitis C Virus Replicon Presents a Higher Barrier to Resistance to Nucleoside Analogs than to Nonnucleoside Polymerase or Protease Inhibitors
Results indicate that the HCV replicon presents a higher barrier to the selection of resistance to nucleoside inhibitors than to nonnucleoside or protease inhibitors, which could have a clear clinical benefit through the delay of resistance emergence.
Selected Replicon Variants with Low-Level In Vitro Resistance to the Hepatitis C Virus NS5B Polymerase Inhibitor PSI-6130 Lack Cross-Resistance with R1479
- S. Ali, V. Lévêque, Wen-Rong Jiang
- Biology, MedicineAntimicrobial Agents and Chemotherapy
- 6 October 2008
PSI-6130 presents a high barrier to resistance selection in vitro, selects for variants exhibiting only low-level resistance, and lacks cross-resistance with R1479, supporting the continued development of the prodrug R7128 as a therapeutic agent for the treatment of HCV infection.
In vitro selected Con1 subgenomic replicons resistant to 2'-C-methyl-cytidine or to R1479 show lack of cross resistance.
Resistance profile of the human immunodeficiency virus type 1 reverse transcriptase inhibitor abacavir (1592U89) after monotherapy and combination therapy. CNA2001 Investigative Group.
Abacavir (1592U89) is a nucleoside inhibitor of human immunodeficiency virus (HIV) type 1 reverse transcriptase (RT). Resistance to abacavir was studied with abacavir alone and with abacavir in…
Significance of amino acid variation at human immunodeficiency virus type 1 reverse transcriptase residue 210 for zidovudine susceptibility
The L210W mutation appears to be of marginal significance, conferring approximately two- to fourfold-reduced sensitivity to AZT compared with similar AZT-resistant genomes with L-210.
2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups*
- K. Klumpp, G. Kalayanov, D. B. Smith
- Biology, ChemistryJournal of Biological Chemistry
- 14 November 2007
Two novel nucleoside triphosphate analogs are described, which are efficiently incorporated into nascent RNA by the RNA-dependent RNA polymerase NS5B of hepatitis C virus (HCV), causing chain termination, despite the lack of α-hydroxy moieties.
Essential Role of the N-terminal Domain in the Regulation of RIG-I ATPase Activity*
Overall, these results show a direct correlation between RNA binding and ATPase enzymatic function leading to signal transduction and suggest that a tight control of ATPase activity by the CARDs prevents RIG-I signaling in the absence of viral RNA.
Selection and Characterization of Replicon Variants Dually Resistant to Thumb- and Palm-Binding Nonnucleoside Polymerase Inhibitors of the Hepatitis C Virus
These findings demonstrate the selection of replicon variants dually resistant to two NS5B polymerase inhibitors binding to different sites of the enzyme, and provide initial insights into the in vitro mutational threshold of the HCV NS5 B polymerase and the potential impact of viral fitness on theselection of multiple-resistant mutants.