ArticlePLoS biology2020
Rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2C.
Article in PLoS biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 29 citations in OpenAlex.
- Targeting Picornavirus Nonstructural 2C Protein: Structure, Function, and Antiviral Discovery.ACS infectious diseases · 2026Review
- Advances in Antiviral Drug Development Targeting Enteroviruses: From Viral Proteins to Host Factors.Viruses · 2026Review
- Non-polio enterovirus infection and electrophysiological changes in human iPSC-derived neural networks.EBioMedicine · 2026Article
- Rational design and in vivo validation of capsid inhibitors for enterovirus D68.Nature communications · 2026Article
- Antiviral candidates for enterovirus 71: targeting viral proteome and stage-specific lifecycle interventions.Virology journal · 2025Review
- Review
- Non-polio enteroviruses compromise the electrophysiology of a human iPSC-derived neural network.bioRxiv : the preprint server for biology · 2025Article
- Design of a Fluorescence Polarization Probe for Enterovirus 2C Proteins.Journal of medicinal chemistry · 2025Article
- ZYG11B suppresses multiple enteroviruses by triggering viral VP1 degradation.Journal of virology · 2025Article
- Emerging Therapeutics in the Fight Against EV-D68: A Review of Current Strategies.Influenza and other respiratory viruses · 2024Review
- Advances in anti-EV-A71 drug development research.Journal of advanced research · 2024Review
- Picornavirus 2C proteins: structure-function relationships and interactions with host factors.Frontiers in cellular and infection microbiology · 2024Review
- Vemurafenib Inhibits Acute and Chronic Enterovirus Infection by Affecting Cellular Kinase Phosphatidylinositol 4-Kinase Type IIIβ.Microbiology spectrum · 2023Article
- Direct-Acting Antivirals and Host-Targeting Approaches against Enterovirus B Infections: Recent Advances.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Animal Models of Enterovirus D68 Infection and Disease.Journal of virology · 2022Review
- Enterovirus A71 antivirals: Past, present, and future.Acta pharmaceutica Sinica. B · 2022Article
- Fluoxetine targets an allosteric site in the enterovirus 2C AAA+ ATPase and stabilizes a ring-shaped hexameric complex.Science advances · 2022Article
- Structure Prediction and Potential Inhibitors Docking of Enterovirus 2C Proteins.Frontiers in microbiology · 2022Article
- Review
- Discovery of Potent and Broad-Spectrum Pyrazolopyridine-Containing Antivirals against Enteroviruses D68, A71, and Coxsackievirus B3 by Targeting the Viral 2C Protein.Journal of medicinal chemistry · 2021Article
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
There is a great need for antiviral drugs to treat enterovirus (EV) and rhinovirus (RV) infections, which can be severe and occasionally life-threatening. The conserved nonstructural protein 2C, which is an AAA+ ATPase, is a promising target for drug development. Here, we present a structure-activity relationship study of a previously identified compound that targets the 2C protein of EV-A71 and several EV-B species members, but not poliovirus (PV) (EV-C species). This compound is structurally related to the Food and Drug Administration (FDA)-approved drug fluoxetine-which also targets 2C-but has favorable chemical properties. We identified several compounds with increased antiviral potency and broadened activity. Four compounds showed broad-spectrum EV and RV activity and inhibited contemporary strains of emerging EVs of public health concern, including EV-A71, coxsackievirus (CV)-A24v, and EV-D68. Importantly, unlike (S)-fluoxetine, these compounds are no longer neuroactive. By raising resistant EV-A71, CV-B3, and EV-D68 variants against one of these inhibitors, we identified novel 2C resistance mutations. Reverse engineering of these mutations revealed a conserved mechanism of resistance development. Resistant viruses first acquired a mutation in, or adjacent to, the α2 helix of 2C. This mutation disrupted compound binding and provided drug resistance, but this was at the cost of viral fitness. Additional mutations at distantly localized 2C residues were then acquired to increase resistance and/or to compensate for the loss of fitness. Using computational methods to identify solvent accessible tunnels near the α2 helix in the EV-A71 and PV 2C crystal structures, a conserved binding pocket of the inhibitors is proposed.
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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.