Ricos, M.G., Cole, B.A., Hussain, R. et al. (7 more authors) (2025) Identification of New KCNT1-Epilepsy Drugs by In Silico, Cell, and Drosophila Modeling. Annals of Neurology. ISSN: 0364-5134
Abstract
Objective Hyperactive KCNT1 potassium channels, caused by gain-of-function mutations, are associated with a range of epilepsy disorders. Patients typically experience drug-resistant seizures and, in cases with infantile onset, developmental regression can follow. KCNT1-related disorders include epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. There are currently no effective treatments for KCNT1 epilepsies, but suppressing overactive channels poses a potential strategy.
Methods Using the KCNT1 channel structure we in silico screened a library of known drugs for those predicted to block the channel pore to inhibit channel activity. Cellular KCNT1 channel inhibition was analyzed using electrophysiology and Drosophila bang-sensitive assays were used to analyze seizure suppression. Brain penetration of one drug was analyzed using liquid chromatography–mass spectrometry in a mouse.
Results Eight known drugs were investigated in vitro for their effects on patient-specific mutant KCNT1 channels, with 4 drugs showing significant reduction of K+ current amplitudes. The action of the 4 drugs was then analyzed in vivo and 2 were found to reduce the seizure phenotype in humanized Drosophila KCNT1 epilepsy models. One drug, antrafenine, was shown to cross the blood–brain barrier in mice.
Interpretation This study identified a known drug, antrafenine, that reduces KCNT1 channel activity, reduces seizure activity in Drosophila, and crosses the blood–brain barrier in the mouse, suggesting its potential applicability as a new treatment for KCNT1 epilepsy. The sequential in silico, in vitro, and in vivo mechanism-based drug selection strategy used here may have broader application for other human disorders where a disease mechanism has been identified. ANN NEUROL 2025
Metadata
| Item Type: | Article |
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| Authors/Creators: |
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| Copyright, Publisher and Additional Information: | © 2025 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
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| Institution: | The University of Leeds |
| Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
| Date Deposited: | 03 Sep 2025 13:38 |
| Last Modified: | 07 Oct 2025 15:36 |
| Status: | Published online |
| Publisher: | Wiley |
| Identification Number: | 10.1002/ana.78031 |
| Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:231108 |

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