ArticlePloS one2016
Biochemical Effect of Resistance Mutations against Synergistic Inhibitors of RSV RNA Polymerase.
Article in PloS one, 2016. 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, 34 citations in OpenAlex.
- Trial
- A comprehensive look at Respiratory Syncytial Virus (RSV): from pathogenesis to prevention.Tropical diseases, travel medicine and vaccines · 2026Review
- Review
- Discovery of a non-nucleoside inhibitor that binds to a novel site in the palm domain of the respiratory syncytial virus RNA-dependent RNA polymerase.Journal of virology · 2025Article
- Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys.Nature communications · 2025Article
- Mechanism of Inhibition of the Active Triphosphate Form of 2'-α-Fluoro,2'-β-bromouridine against Yellow Fever Virus RNA-Dependent RNA Polymerase.ACS infectious diseases · 2025Article
- Review
- Structural basis of paramyxo- and pneumovirus polymerase inhibition by non-nucleoside small-molecule antivirals.Antimicrobial agents and chemotherapy · 2024Review
- Inter and intra-host diversity of RSV in hematopoietic stem cell transplant adults with normal and delayed viral clearance.Virus evolution · 2024Article
- Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2.Topics in current chemistry (Cham) · 2023Review
- Respiratory Syncytial Virus Phosphoprotein Residue S156 Plays a Role in Regulating Genome Transcription and Replication.Journal of virology · 2021Article
- Discovery of a Novel Respiratory Syncytial Virus Replication Inhibitor.Antimicrobial agents and chemotherapy · 2021Article
- Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro.Molecules (Basel, Switzerland) · 2021Article
- RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic.European journal of medicinal chemistry · 2021Review
- Inhibition of viral RNA-dependent RNA polymerases with clinically relevant nucleotide analogs.The Enzymes · 2021Article
- Article
- Targeting the Respiratory Syncytial Virus NAntimicrobial agents and chemotherapy · 2020Article
- Cryo-EM structure of the respiratory syncytial virus RNA polymerase.Nature communications · 2020Article
- Article
- Nucleoside analogues for the treatment of coronavirus infections.Current opinion in virology · 2019Review
Corrections and comments
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ALS-8112 is the parent molecule of ALS-8176, a first-in-class nucleoside analog prodrug effective in the clinic against respiratory syncytial virus (RSV) infection. The antiviral activity of ALS-8112 is mediated by its 5'-triphosphate metabolite (ALS-8112-TP, or 2'F-4'ClCH2-cytidine triphosphate) inhibiting the RNA polymerase activity of the RSV L-P protein complex through RNA chain termination. Four amino acid mutations in the RNA-dependent RNA polymerase (RdRp) domain of L (QUAD: M628L, A789V, L795I, and I796V) confer in vitro resistance to ALS-8112-TP by increasing its discrimination relative to natural CTP. In this study, we show that the QUAD mutations specifically recognize the ClCH2 group of ALS-8112-TP. Among the four mutations, A789V conferred the greatest resistance phenotype, which was consistent with its putative position in the active site of the RdRp domain. AZ-27, a non-nucleoside inhibitor of RSV, also inhibited the RdRp activity, with decreased inhibition potency in the presence of the Y1631H mutation. The QUAD mutations had no effect on the antiviral activity of AZ-27, and the Y1631H mutation did not significantly increase the discrimination of ALS-8112-TP. Combining ALS-8112 with AZ-27 in vitro resulted in significant synergistic inhibition of RSV replication. Overall, this is the first mechanistic study showing a lack of cross-resistance between mutations selected by different classes of RSV polymerase inhibitors acting in synergy, opening the door to future potential combination therapies targeting different regions of the L protein.
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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.