ArticlePLoS pathogens2015
Molecular Basis for the Selective Inhibition of Respiratory Syncytial Virus RNA Polymerase by 2'-Fluoro-4'-Chloromethyl-Cytidine Triphosphate.
Article in PLoS pathogens, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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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.
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Who cites it
53 citing papers in PubMed, 91 citations in OpenAlex.
- Trial
- Towards broader-spectrum direct-acting antivirals against RNA viruses.Nature reviews. Microbiology · 2026Review
- Substrate and target selectivity of 4'-fluoroadenosine against viral and host polymerases.The Journal of biological chemistry · 2026Article
- Donor-derived airway air-liquid interface model for high-throughput screening of antiviral combinations with concurrent analysis of antiviral efficacy and epithelial toxicity using ciliR.ERJ open research · 2026Article
- Human telomerase reverse transcriptase supports respiratory syncytial virus replication.Communications biology · 2026Article
- Structural Mapping of Surveillance Data Reveals Conservation of NNI Binding Site in RSV L Protein.Pathogens (Basel, Switzerland) · 2026Article
- Status of advanced respiratory syncytial virus antiviral therapeutics 2025.Current opinion in virology · 2025Review
- Review
- Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys.Nature communications · 2025Article
- Mechanism and spectrum of inhibition of viral polymerases by 2'-deoxy-2'-β-fluoro-4'-azidocytidine or azvudine.NAR molecular medicine · 2025Article
- Review
- Advances in development of antiviral strategies against respiratory syncytial virus.Acta pharmaceutica Sinica. B · 2025Review
- In Vitro Biochemical Assays to Study Respiratory Syncytial Virus Polymerase Activities.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Design and Execution of In Vitro Polymerase Assays for Measles Virus and Related Mononegaviruses.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Structural and mechanistic insights into the inhibition of respiratory syncytial virus polymerase by a non-nucleoside inhibitor.Communications biology · 2023Article
- In Silico Identification and In Vitro Validation of Repurposed Compounds Targeting the RSV Polymerase.Microorganisms · 2023Article
- Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2.Topics in current chemistry (Cham) · 2023Review
- Biochemistry of the Respiratory Syncytial Virus L Protein Embedding RNA Polymerase and Capping Activities.Viruses · 2023Review
- Nucleoside analogs for management of respiratory virus infections: mechanism of action and clinical efficacy.Current opinion in virology · 2022Review
- Orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase.Science advances · 2022Article
Corrections and comments
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Authors and funding
23 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections, yet no vaccines or effective therapeutics are available. ALS-8176 is a first-in-class nucleoside analog prodrug effective in RSV-infected adult volunteers, and currently under evaluation in hospitalized infants. Here, we report the mechanism of inhibition and selectivity of ALS-8176 and its parent ALS-8112. ALS-8176 inhibited RSV replication in non-human primates, while ALS-8112 inhibited all strains of RSV in vitro and was specific for paramyxoviruses and rhabdoviruses. The antiviral effect of ALS-8112 was mediated by the intracellular formation of its 5'-triphosphate metabolite (ALS-8112-TP) inhibiting the viral RNA polymerase. ALS-8112 selected for resistance-associated mutations within the region of the L gene of RSV encoding the RNA polymerase. In biochemical assays, ALS-8112-TP was efficiently recognized by the recombinant RSV polymerase complex, causing chain termination of RNA synthesis. ALS-8112-TP did not inhibit polymerases from host or viruses unrelated to RSV such as hepatitis C virus (HCV), whereas structurally related molecules displayed dual RSV/HCV inhibition. The combination of molecular modeling and enzymatic analysis showed that both the 2'F and the 4'ClCH2 groups contributed to the selectivity of ALS-8112-TP. The lack of antiviral effect of ALS-8112-TP against HCV polymerase was caused by Asn291 that is well-conserved within positive-strand RNA viruses. This represents the first comparative study employing recombinant RSV and HCV polymerases to define the selectivity of clinically relevant nucleotide analogs. Understanding nucleotide selectivity towards distant viral RNA polymerases could not only be used to repurpose existing drugs against new viral infections, but also to design novel molecules.
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