ArticleProceedings of the National Academy of Sciences of the United States of America2011
Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV).
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 94 citations in OpenAlex.
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- Development of an Antiviral Ion-Activated In Situ Gel Containing 18β-Glycyrrhetinic Acid: A Promising Alternative against Respiratory Syncytial Virus.Pharmaceutics · 2023Article
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- Safety and Efficacy of Vidofludimus Calcium in Patients Hospitalized with COVID-19: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial.Infectious diseases and therapy · 2022Article
- Brequinar and dipyridamole in combination exhibits synergistic antiviral activity against SARS-CoV-2 in vitro: Rationale for a host-acting antiviral treatment strategy for COVID-19.Antiviral research · 2022Article
- Development of accelerated high-throughput antiviral screening systems for emerging orthomyxoviruses.Antiviral research · 2022Article
- In silico virtual screening of lead compounds for major antigenic sites in respiratory syncytial virus fusion protein.Emergent materials · 2022Article
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- Discovery of a Novel Respiratory Syncytial Virus Replication Inhibitor.Antimicrobial agents and chemotherapy · 2021Article
- DHODH and cancer: promising prospects to be explored.Cancer & metabolism · 2021Review
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- Inhibition of porcine epidemic diarrhea virus (PEDV) replication by A77 1726 through targeting JAK and Src tyrosine kinases.Virology · 2020Article
- Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism.Cell chemical biology · 2020Article
- Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.Cell chemical biology · 2020Article
- Advances and challenges in the prevention and treatment of COVID-19.International journal of medical sciences · 2020Review
- Discovery of small molecule inhibitors of human uridine-cytidine kinase 2 by high-throughput screening.Bioorganic & medicinal chemistry letters · 2019Article
- Overview of Current Therapeutics and Novel Candidates Against Influenza, Respiratory Syncytial Virus, and Middle East Respiratory Syndrome Coronavirus Infections.Frontiers in microbiology · 2019Review
- Novel AR-12 derivatives, P12-23 and P12-34, inhibit flavivirus replication by blocking host de novo pyrimidine biosynthesis.Emerging microbes & infections · 2018Article
Corrections and comments
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Authors and funding
27 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.
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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.