ArticleAntimicrobial agents and chemotherapy2016
Identification of a Pyridoxine-Derived Small-Molecule Inhibitor Targeting Dengue Virus RNA-Dependent RNA Polymerase.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 39 citations in OpenAlex.
- Identification of potential inhibitors of dengue virus ns5 methyltransferase and polymerase domains through virtual screening and molecular dynamics studies.Journal of molecular modeling · 2026Article
- Article
- Development in the Inhibition of Dengue Proteases as Drug Targets.Current medicinal chemistry · 2024Review
- Design, Synthesis, Evaluation and Molecular Dynamics Simulation of Dengue Virus NS5-RdRp Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Identification of Polyphenol Derivatives as Novel SARS-CoV-2 and DENV Non-Nucleoside RdRp Inhibitors.Molecules (Basel, Switzerland) · 2022Article
- Seeking heterocyclic scaffolds as antivirals against dengue virus.European journal of medicinal chemistry · 2022Review
- Molecular docking and dynamics studies of Nicotinamide Riboside as a potential multi-target nutraceutical against SARS-CoV-2 entry, replication, and transcription: A new insight.Journal of molecular structure · 2022Article
- Recent advances in the discovery of potent RNA-dependent RNA-polymerase (RdRp) inhibitors targeting viruses.RSC medicinal chemistry · 2021Review
- [1,2,4]Triazolo[1,5-a]pyrimidine derivative (Mol-5) is a new NS5-RdRp inhibitor of DENV2 proliferation and DENV2-induced inflammation.Acta pharmacologica Sinica · 2020Article
- Sophoraflavenone G Restricts Dengue and Zika Virus Infection via RNA Polymerase Interference.Viruses · 2017Article
- Evaluation of Sofosbuvir (β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine) as an inhibitor of Dengue virus replication<sup/>.Scientific reports · 2017Article
- Purification of Zika virus RNA-dependent RNA polymerase and its use to identify small-molecule Zika inhibitors.The Journal of antimicrobial chemotherapy · 2017Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
The viral RNA-dependent RNA polymerase (RdRp) activity of the dengue virus (DENV) NS5 protein is an attractive target for drug design. Here, we report the identification of a novel class of inhibitor (i.e., an active-site metal ion chelator) that acts against DENV RdRp activity. DENV RdRp utilizes a two-metal-ion mechanism of catalysis; therefore, we constructed a small library of compounds, through mechanism-based drug design, aimed at chelating divalent metal ions in the catalytic site of DENV RdRp. We now describe a pyridoxine-derived small-molecule inhibitor that targets DENV RdRp and show that 5-benzenesulfonylmethyl-3-hydroxy-4-hydroxymethyl-pyridine-2-carboxylic acid hydroxyamide (termed DMB220) inhibited the RdRp activity of DENV serotypes 1 to 4 at low micromolar 50% inhibitory concentrations (IC50s of 5 to 6.7 μM) in an enzymatic assay. The antiviral activity of DMB220 against DENV infection was also verified in a cell-based assay and showed a 50% effective concentration (EC50) of <3 μM. Enzyme assays proved that DMB220 was competitive with nucleotide incorporation. DMB220 did not inhibit the enzymatic activity of recombinant HIV-1 reverse transcriptase and showed only weak inhibition of HIV-1 integrase strand transfer activity, indicating high specificity for DENV RdRp. S600T substitution in the DENV RdRp, which was previously shown to confer resistance to nucleoside analogue inhibitors (NI), conferred 3-fold hypersusceptibility to DMB220, and enzymatic analyses showed that this hypersusceptibility may arise from the decreased binding/incorporation efficiency of the natural NTP substrate without significantly impacting inhibitor binding. Thus, metal ion chelation at the active site of DENV RdRp represents a viable anti-DENV strategy, and DMB220 is the first of a new class of DENV inhibitor.
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