ArticleScience advances2022
Orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase.
Article in Science advances, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Direct interaction between RSV polymerase L and active Rab11a mediates viral ribonucleoprotein transport to assembly sites.PLoS pathogens · 2026Article
- Catching our breath: development of interventions and therapies for respiratory syncytial virus.Microbiology and molecular biology reviews : MMBR · 2026Review
- Identification and characterization of novel chikungunya virus polymerase inhibitors.Journal of virology · 2026Article
- Developmental candidate GHP-88310/EIDD-3608 with high tolerability and oral efficacy in measles and respiratory paramyxovirus models.Science advances · 2026Article
- Article
- Preclinical characterization and anti-RSV efficacy of an oral C-nucleoside derivative.Acta pharmaceutica Sinica. B · 2025Article
- Status of advanced respiratory syncytial virus antiviral therapeutics 2025.Current opinion in virology · 2025Review
- 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
- Current antiviral therapies and promising drug candidates against respiratory syncytial virus infection.Virologica Sinica · 2025Review
- Serial Adaptation of Viruses for Reduced Susceptibility Profiling.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Respiratory syncytial virus: health burden, disease prevention, and treatment-recent progress and lessons learned.microLife · 2025Review
- In Vitro Biochemical Assays to Study Respiratory Syncytial Virus Polymerase Activities.Methods in molecular biology (Clifton, N.J.) · 2025Article
- The Development of Animal Models for Respiratory Syncytial Virus (RSV) Infection and Enhanced RSV Disease.Viruses · 2024Review
- Structural basis of paramyxo- and pneumovirus polymerase inhibition by non-nucleoside small-molecule antivirals.Antimicrobial agents and chemotherapy · 2024Review
- 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
- Conserved allosteric inhibitory site on the respiratory syncytial virus and human metapneumovirus RNA-dependent RNA polymerases.Communications biology · 2023Article
- Biochemistry of the Respiratory Syncytial Virus L Protein Embedding RNA Polymerase and Capping Activities.Viruses · 2023Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory infections in infants and the immunocompromised, yet no efficient therapeutic exists. We have identified the AVG class of allosteric inhibitors of RSV RNA synthesis. Here, we demonstrate through biolayer interferometry and in vitro RNA-dependent RNA polymerase (RdRP) assays that AVG compounds bind to the viral polymerase, stalling the polymerase in initiation conformation. Resistance profiling revealed a unique escape pattern, suggesting a discrete docking pose. Affinity mapping using photoreactive AVG analogs identified the interface of polymerase core, capping, and connector domains as a molecular target site. A first-generation lead showed nanomolar potency against RSV in human airway epithelium organoids but lacked in vivo efficacy. Docking pose-informed synthetic optimization generated orally efficacious AVG-388, which showed potent efficacy in the RSV mouse model when administered therapeutically. This study maps a druggable target in the RSV RdRP and establishes clinical potential of the AVG chemotype against RSV disease.
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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.