ArticleACS chemical biology2013
Crystallographic fragment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors.
Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 84 citations in OpenAlex.
- Article
- Enhancing the Outcome of Crystallographic Fragment Screening by Choosing the Optimal Protein Crystal Form.Small science · 2026Article
- Establishment of an at-line nanofractionation-based screening platform for rapid identification of influenza PAJournal of pharmaceutical analysis · 2026Article
- Pharmacophores of Influenza Virus PA Endonuclease Inhibitors.Advances in experimental medicine and biology · 2026Review
- Antiviral strategies against influenza virus: an update on approved and innovative therapeutic approaches.Cellular and molecular life sciences : CMLS · 2025Review
- A novel compound to overcome influenza drug resistance in endonuclease inhibitors.Molecular diversity · 2024Article
- Emerging drug design strategies in anti-influenza drug discovery.Acta pharmaceutica Sinica. B · 2023Review
- Article
- Halo Library, a Tool for Rapid Identification of Ligand Binding Sites on Proteins Using Crystallographic Fragment Screening.Journal of medicinal chemistry · 2023Article
- Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors.ACS medicinal chemistry letters · 2023Article
- Contemporary medicinal chemistry strategies for the discovery and optimization of influenza inhibitors targeting vRNP constituent proteins.Acta pharmaceutica Sinica. B · 2022Review
- Computational Prediction of the Binding Pose of Metal-Binding Pharmacophores.ACS medicinal chemistry letters · 2022Article
- Photorelease of a metal-binding pharmacophore from a Ru(II) polypyridine complex.Dalton transactions (Cambridge, England : 2003) · 2021Article
- Rapid in vitro assays for screening neutralizing antibodies and antivirals against SARS-CoV-2.Journal of virological methods · 2021Article
- Kinase inhibitor roscovitine as a PB2 cap-binding inhibitor against influenza a virus replication.Biochemical and biophysical research communications · 2020Article
- Article
- Aryl and Arylalkyl Substituted 3-Hydroxypyridin-2(1H)-ones: Synthesis and Evaluation as Inhibitors of Influenza A Endonuclease.ChemMedChem · 2019Article
- Targeting Metalloenzymes for Therapeutic Intervention.Chemical reviews · 2019Review
- Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.Journal of medicinal chemistry · 2018Article
- Protein-Structure Assisted Optimization of 4,5-Dihydroxypyrimidine-6-Carboxamide Inhibitors of Influenza Virus Endonuclease.Scientific reports · 2017Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
Abstract
Seasonal and pandemic influenza viruses continue to be a leading global health concern. Emerging resistance to the current drugs and the variable efficacy of vaccines underscore the need for developing new flu drugs that will be broadly effective against wild-type and drug-resistant influenza strains. Here, we report the discovery and development of a class of inhibitors targeting the cap-snatching endonuclease activity of the viral polymerase. A high-resolution crystal form of pandemic 2009 H1N1 influenza polymerase acidic protein N-terminal endonuclease domain (PAN) was engineered and used for fragment screening leading to the identification of new chemical scaffolds binding to the PAN active site cleft. During the course of screening, binding of a third metal ion that is potentially relevant to endonuclease activity was detected in the active site cleft of PAN in the presence of a fragment. Using structure-based optimization, we developed a highly potent hydroxypyridinone series of compounds from a fragment hit that defines a new mode of chelation to the active site metal ions. A compound from the series demonstrating promising enzymatic inhibition in a fluorescence-based enzyme assay with an IC50 value of 11 nM was found to have an antiviral activity (EC50) of 11 μM against PR8 H1N1 influenza A in MDCK cells.
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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.