ArticleAntiviral research2011
Activity and the metabolic activation pathway of the potent and selective hepatitis C virus pronucleotide inhibitor PSI-353661.
Article in Antiviral research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
24 citing papers in PubMed, 46 citations in OpenAlex.
- 2'-Fluorinated nucleoside chemistry for new drug discovery: achievements and prospects.National science review · 2024Review
- Tissue-Specific Proteomics Analysis of Anti-COVID-19 Nucleoside and Nucleotide Prodrug-Activating Enzymes Provides Insights into the Optimization of Prodrug Design and Pharmacotherapy Strategy.ACS pharmacology & translational science · 2021Article
- A Cyclic Phosphoramidate Prodrug of 2'-Deoxy-2'-Fluoro-2'-Antimicrobial agents and chemotherapy · 2020Article
- The Enzyme-Free Release of Nucleotides from Phosphoramidates Depends Strongly on the Amino Acid.Angewandte Chemie (International ed. in English) · 2020Article
- Metabolic Efficacy of Phosphate Prodrugs and the Remdesivir Paradigm.ACS pharmacology & translational science · 2020Review
- Intracellular metabolism and potential cardiotoxicity of a β-D-2'-Nucleosides, nucleotides & nucleic acids · 2020Article
- Preclinical evaluation of AT-527, a novel guanosine nucleotide prodrug with potent, pan-genotypic activity against hepatitis C virus.PloS one · 2020Article
- Phosphonamidate Prodrugs of a Butyrophilin Ligand Display Plasma Stability and Potent Vγ9 Vδ2 T Cell Stimulation.Journal of medicinal chemistry · 2018Article
- The expanding role of prodrugs in contemporary drug design and development.Nature reviews. Drug discovery · 2018Review
- Role of Mitochondrial RNA Polymerase in the Toxicity of Nucleotide Inhibitors of Hepatitis C Virus.Antimicrobial agents and chemotherapy · 2016Article
- Synthesis, Hydrolysis, and Protonation-Promoted Intramolecular Reductive Breakdown of Potential NRTIs: Stavudine α-P-Borano-γ-P-N-L-tryptophanyltriphosphates.Molecules (Basel, Switzerland) · 2015Article
- Prodrugs of phosphonates and phosphates: crossing the membrane barrier.Topics in current chemistry · 2015Review
- Implications of efficient hepatic delivery by tenofovir alafenamide (GS-7340) for hepatitis B virus therapy.Antimicrobial agents and chemotherapy · 2015Article
- Undesired versus designed enzymatic cleavage of linkers for liver targeting.Bioorganic & medicinal chemistry letters · 2014Article
- Chutes and ladders in hepatitis C nucleoside drug development.Antiviral research · 2014Review
- Metabolism and pharmacokinetics of the anti-hepatitis C virus nucleotide prodrug GS-6620.Antimicrobial agents and chemotherapy · 2014Article
- Highlights in antiviral drug research: antivirals at the horizon.Medicinal research reviews · 2013Review
- An in vitro evaluation of antioxidant and colonic microbial profile levels following mushroom consumption.BioMed research international · 2013Article
- Calamitous HCV trial casts shadow over nucleoside drugs.Nature biotechnology · 2012Article
- Metabolic activation of the anti-hepatitis C virus nucleotide prodrug PSI-352938.Antimicrobial agents and chemotherapy · 2012Article
Corrections and comments
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Authors and funding
18 authors at 3 institutions in 1 country.
Funding
Abstract
PSI-353661, a phosphoramidate prodrug of 2'-deoxy-2'-fluoro-2'-C-methylguanosine-5'-monophosphate, is a highly active inhibitor of genotype 1a, 1b, and 2a HCV RNA replication in the replicon assay and of genotype 1a and 2a infectious virus replication. PSI-353661 is active against replicons harboring the NS5B S282T or S96T/N142T amino acid alterations that confer decreased susceptibility to nucleoside/tide analogs as well as mutations that confer resistance to non-nucleoside inhibitors of NS5B. Replicon clearance studies show that PSI-353661 was able to clear cells of HCV replicon RNA and prevent a rebound in replicon RNA. PSI-353661 showed no toxicity toward bone marrow stem cells or mitochondrial toxicity. The metabolism to the active 5'-triphosphate involves hydrolysis of the carboxyl ester by cathepsin A (Cat A) and carboxylesterase 1 (CES1) followed by a putative nucleophilic attack on the phosphorus by the carboxyl group resulting in the elimination of phenol and the alaninyl phosphate metabolite, PSI-353131. Histidine triad nucleotide-binding protein 1 (Hint 1) then removes the amino acid moiety, which is followed by hydrolysis of the methoxyl group at the O(6)-position of the guanine base by adenosine deaminase-like protein 1 (ADAL1) to give 2'-deoxy-2'-fluoro-2'-C-methylguanosine-5'-monophosphate. The monophosphate is phosphorylated to the diphosphate by guanylate kinase. Nucleoside diphosphate kinase is the primary enzyme involved in phosphorylation of the diphosphate to the active triphosphate, PSI-352666. PSI-352666 is equally active against wild-type NS5B and NS5B containing the S282T amino acid alteration.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.