ArticleNature chemical biology2025
Small molecule inhibits KCNQ channels with a non-blocking mechanism.
Article in Nature chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Structural and kinetic mechanisms of state-dependent potassium channel inhibition.Science advances · 2026Article
- Cannabidiol inhibits both human KActa pharmacologica Sinica · 2026Article
- KCNQ2 Gain-of-Function Mutation Presenting as Respiratory Dysfunction and Non-epileptic Myoclonus.Cureus · 2026Article
- Cholesterol and Cholesterol-Derived Molecules Differentially Modulate Neuronal Kv7.2/7.3 Channels.Archiv der Pharmazie · 2026Article
- A single allosteric site merges activation, modulation and inhibition in TRPM5.Nature chemical biology · 2026Article
- From Flux to Function: Extracting Mechanistic Insights from Ion Channels via I-V and I-μ Analyses.bioRxiv : the preprint server for biology · 2025Article
- Bridging prion biology and Alzheimer's disease: from pathogenic seeds to precision therapeutics.Frontiers in molecular neuroscience · 2025Review
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Authors and funding
17 authors.
Funding
Abstract
Voltage-gated ion channels (VGICs) are crucial targets for neuropsychiatric therapeutics owing to their role in controlling neuronal excitability and the established link between their dysfunction and neurological diseases, highlighting the importance of identifying modulators with distinct mechanisms. Here we report two small-molecule modulators with the same chemical scaffold, Ebio2 and Ebio3, targeting a potassium channel KCNQ2, with opposite effects: Ebio2 acts as a potent activator, whereas Ebio3 serves as a potent and selective inhibitor. Guided by cryogenic electron microscopy, patch-clamp recordings and molecular dynamics simulations, we reveal that Ebio3 attaches to the outside of the inner gate, employing a unique non-blocking inhibitory mechanism that directly squeezes the S6 pore helix to inactivate the KCNQ2 channel. Ebio3 also showed efficacy in inhibiting currents of KCNQ2 pathogenic gain-of-function mutations, presenting an avenue for VGIC-targeted therapies. Overall, these findings contribute to the understanding of KCNQ2 inhibition and provide insights into developing selective, non-blocking VGIC inhibitors.
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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.