ArticleAntimicrobial agents and chemotherapy2013
A novel, broad-spectrum inhibitor of enterovirus replication that targets host cell factor phosphatidylinositol 4-kinase IIIβ.
Article in Antimicrobial agents and chemotherapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 114 citations in OpenAlex.
- Phosphoinositide kinases in cancer: from molecular mechanisms to therapeutic opportunities.Nature reviews. Cancer · 2025Review
- ZYG11B suppresses multiple enteroviruses by triggering viral VP1 degradation.Journal of virology · 2025Article
- Inositol metabolism as a broad-spectrum antiviral target.Frontiers in microbiology · 2025Review
- Syntaxin 17 recruitment to mature autophagosomes is temporally regulated by PI4P accumulation.eLife · 2024Article
- Chemoproteomics enables identification of coatomer subunit zeta-1 targeted by a small molecule for enterovirus A71 inhibition.MedComm · 2024Article
- The activation of the adaptor protein STING depends on its interactions with the phospholipid PI4P.Science signaling · 2024Article
- A DNA Plasmid-Based Approach for Efficient Synthesis of Sacbrood Virus Infectious Clones within Host Cells.Viruses · 2023Article
- Vemurafenib Inhibits Acute and Chronic Enterovirus Infection by Affecting Cellular Kinase Phosphatidylinositol 4-Kinase Type IIIβ.Microbiology spectrum · 2023Article
- A Plethora of Functions Condensed into Tiny Phospholipids: The Story of PI4P and PI(4,5)PCells · 2023Review
- Beyond PI3Ks: targeting phosphoinositide kinases in disease.Nature reviews. Drug discovery · 2023Review
- Article
- ORP9 and ORP10 form a heterocomplex to transfer phosphatidylinositol 4-phosphate at ER-TGN contact sites.Cellular and molecular life sciences : CMLS · 2023Article
- Construction of a Vero Cell Line Expressing Human ICAM1 for the Development of Rhinovirus Vaccines.Viruses · 2022Article
- High-Order Epistasis and Functional Coupling of Infection Steps Drive Virus Evolution toward Independence from a Host Pathway.Microbiology spectrum · 2021Article
- Novel capsid binder and PI4KIIIbeta inhibitors for EV-A71 replication inhibition.Scientific reports · 2021Article
- Picornaviruses: A View from 3A.Viruses · 2021Review
- Review
- Dissecting distinct proteolytic activities of FMDV Lpro implicates cleavage and degradation of RLR signaling proteins, not its deISGylase/DUB activity, in type I interferon suppression.PLoS pathogens · 2020Article
- The interplay of autophagy and enterovirus.Seminars in cell & developmental biology · 2020Review
- Host factor prioritization for pan-viral genetic perturbation screens using random intercept models and network propagation.PLoS computational biology · 2020Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Despite their high clinical and socioeconomic impacts, there is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections. Here we report on a novel inhibitor of enterovirus replication, compound 1, 2-fluoro-4-(2-methyl-8-(3-(methylsulfonyl)benzylamino)imidazo[1,2-a]pyrazin-3-yl)phenol. This compound exhibited a broad spectrum of antiviral activity, as it inhibited all tested species of enteroviruses and rhinoviruses, with 50% effective concentrations ranging between 4 and 71 nM. After a lengthy resistance selection process, coxsackievirus mutants resistant to compound 1 were isolated that carried substitutions in their 3A protein. Remarkably, the same substitutions were recently shown to provide resistance to inhibitors of phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), a lipid kinase that is essential for enterovirus replication, suggesting that compound 1 may also target this host factor. Accordingly, compound 1 directly inhibited PI4KIIIβ in an in vitro kinase activity assay. Furthermore, the compound strongly reduced the PI 4-phosphate levels of the Golgi complex in cells. Rescue of coxsackievirus replication in the presence of compound 1 by a mutant PI4KIIIβ carrying a substitution in its ATP-binding pocket revealed that the compound directly binds the kinase at this site. Finally, we determined that an analogue of compound 1, 3-(3-fluoro-4-methoxyphenyl)-2-methyl-N-(pyridin-4-ylmethyl)imidazo[1,2-a]pyrazin-8-amine, is well tolerated in mice and has a dose-dependent protective activity in a coxsackievirus serotype B4-induced pancreatitis model.
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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.