ArticleCommunications biology2023
Structural and mechanistic insights into the inhibition of respiratory syncytial virus polymerase by a non-nucleoside inhibitor.
Article in Communications biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 32 citations in OpenAlex.
- mRNA cap formation by the human respiratory syncytial virus large protein.Nucleic acids research · 2026Article
- Targeting the RSV and hMPV L Protein: Cryo-EM and Structure-Based Approaches to Antiviral Drug Discovery.Biomolecules · 2026Review
- Catching our breath: development of interventions and therapies for respiratory syncytial virus.Microbiology and molecular biology reviews : MMBR · 2026Review
- Small Molecule Inhibition of Mononegavirales RNA Polymerases.Journal of medical virology · 2026Review
- Article
- Structural Mapping of Surveillance Data Reveals Conservation of NNI Binding Site in RSV L Protein.Pathogens (Basel, Switzerland) · 2026Article
- Can plitidepsin be used as an antiviral against RSV?mSphere · 2025Article
- Review
- Molecular characterization of human respiratory syncytial virus in Mexico (season 2023-2024) through whole-genome sequencing.Scientific reports · 2025Article
- 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
- hMPV Outbreaks: Worldwide Implications of a Re-Emerging Respiratory Pathogen.Microorganisms · 2025Review
- Review
- Advances in development of antiviral strategies against respiratory syncytial virus.Acta pharmaceutica Sinica. B · 2025Review
- Article
- In Vitro Biochemical Assays to Study Respiratory Syncytial Virus Polymerase Activities.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Structural basis of paramyxo- and pneumovirus polymerase inhibition by non-nucleoside small-molecule antivirals.Antimicrobial agents and chemotherapy · 2024Review
- Structure of the Nipah virus polymerase phosphoprotein complex.Nature communications · 2024Article
- Structure-Activity Relationship of Oxacyclo- and Triazolo-Containing Respiratory Syncytial Virus Polymerase Inhibitors.ACS medicinal chemistry letters · 2024Article
- How does the polymerase of non-segmented negative strand RNA viruses commit to transcription or genome replication?Journal of virology · 2024Review
- Small Molecule Drugs Targeting Viral Polymerases.Pharmaceuticals (Basel, Switzerland) · 2024Review
Corrections and comments
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Authors and funding
30 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap methylation via the RNA dependent RNA polymerase, capping, and Methyltransferase domains on L. Several nucleoside and non-nucleoside inhibitors have been reported to inhibit this polymerase complex, but the structural details of the exact inhibitor-polymerase interactions have been lacking. Here, we report a non-nucleoside inhibitor JNJ-8003 with sub-nanomolar inhibition potency in both antiviral and polymerase assays. Our 2.9 Å resolution cryo-EM structure revealed that JNJ-8003 binds to an induced-fit pocket on the capping domain, with multiple interactions consistent with its tight binding and resistance mutation profile. The minigenome and gel-based de novo RNA synthesis and primer extension assays demonstrated that JNJ-8003 inhibited nucleotide polymerization at the early stages of RNA transcription and replication. Our results support that JNJ-8003 binding modulates a functional interplay between the capping and RdRp domains, and this molecular insight could accelerate the design of broad-spectrum antiviral drugs.
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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.