ArticleJournal of medicinal chemistry2015
β-D-2'-C-Methyl-2,6-diaminopurine Ribonucleoside Phosphoramidates are Potent and Selective Inhibitors of Hepatitis C Virus (HCV) and Are Bioconverted Intracellularly to Bioactive 2,6-Diaminopurine and Guanosine 5'-Triphosphate Forms.
Article in Journal of medicinal chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Review
- Diastereoselective Synthesis of 2'-Dihalopyrimidine Ribonucleoside Inhibitors of Hepatitis C Virus Replication.ACS omega · 2022Article
- Intracellular metabolism and potential cardiotoxicity of a β-D-2'-Nucleosides, nucleotides & nucleic acids · 2020Article
- Nucleotide Substrate Specificity of Anti-Hepatitis C Virus Nucleoside Analogs for Human Mitochondrial RNA Polymerase.Antimicrobial agents and chemotherapy · 2017Article
- Current therapy for chronic hepatitis C: The role of direct-acting antivirals.Antiviral research · 2017Review
- Substrates and Inhibitors of SAMHD1.PloS one · 2017Article
- Biochemical Characterization of the Active Anti-Hepatitis C Virus Metabolites of 2,6-Diaminopurine Ribonucleoside Prodrug Compared to Sofosbuvir and BMS-986094.Antimicrobial agents and chemotherapy · 2016Article
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
The conversion of selected β-D-2,6-diaminopurine nucleosides (DAPNs) to their phosphoramidate prodrug (PD) substantially blocks the conversion to the G-analog allowing for the generation of two bioactive nucleoside triphosphates (NTPs) in human hepatocytes. A variety of 2'-C-methyl DAPN-PDs were prepared and evaluated for inhibition of HCV viral replication in Huh-7 cells, cytotoxicity in various cell lines, and cellular pharmacology in both Huh-7 and primary human liver cells. The DAPN-PDs were pan-genotypic, effective against various HCV resistant mutants, and resistant variants could not be selected. 2'-C-Me-DAPN-TP and 2'-C-Me-GTP were chain terminators for genotype 1b HCV-pol, and single nucleotide incorporation assays revealed that 2'-C-Me-DAPN-TP was incorporated opposite U. No cytotoxicity was observed with our DAPN-PD when tested up to 50 μM. A novel, DAPN-PD, 15c, has been selected for further evaluation because of its good virologic and toxicologic profile and its ability to deliver two active metabolites, potentially simplifying HCV treatment.
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