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Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated KNa1.1 (KCNT1) Potassium Channel.
iScience. 2020 May 22; 23(5):101100.I

Abstract

Drug-resistant epileptic encephalopathies of infancy have been associated with KCNT1 gain-of-function mutations, which increase the activity of KNa1.1 sodium-activated potassium channels. Pharmacological inhibition of hyperactive KNa1.1 channels by quinidine has been proposed as a stratified treatment, but mostly this has not been successful, being linked to the low potency and lack of specificity of the drug. Here we describe the use of a previously determined cryo-electron microscopy-derived KNa1.1 structure and mutational analysis to identify how quinidine binds to the channel pore and, using computational methods, screened for compounds predicated to bind to this site. We describe six compounds that inhibited KNa1.1 channels with low- and sub-micromolar potencies, likely also through binding in the intracellular pore vestibule. In hERG inhibition and cytotoxicity assays, two compounds were ineffective. These may provide starting points for the development of new pharmacophores and could become tool compounds to study this channel further.

Authors+Show Affiliations

School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.Autifony Srl, Istituto di Ricerca Pediatrica Citta' della Speranza, Corso Stati Uniti, 4f, 35127 Padova, Italy.Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK; School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. Electronic address: j.d.lippiat@leeds.ac.uk.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32408169

Citation

Cole, Bethan A., et al. "Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated KNa1.1 (KCNT1) Potassium Channel." IScience, vol. 23, no. 5, 2020, p. 101100.
Cole BA, Johnson RM, Dejakaisaya H, et al. Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated KNa1.1 (KCNT1) Potassium Channel. iScience. 2020;23(5):101100.
Cole, B. A., Johnson, R. M., Dejakaisaya, H., Pilati, N., Fishwick, C. W. G., Muench, S. P., & Lippiat, J. D. (2020). Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated KNa1.1 (KCNT1) Potassium Channel. IScience, 23(5), 101100. https://doi.org/10.1016/j.isci.2020.101100
Cole BA, et al. Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated KNa1.1 (KCNT1) Potassium Channel. iScience. 2020 May 22;23(5):101100. PubMed PMID: 32408169.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated KNa1.1 (KCNT1) Potassium Channel. AU - Cole,Bethan A, AU - Johnson,Rachel M, AU - Dejakaisaya,Hattapark, AU - Pilati,Nadia, AU - Fishwick,Colin W G, AU - Muench,Stephen P, AU - Lippiat,Jonathan D, Y1 - 2020/04/25/ PY - 2019/11/07/received PY - 2020/04/02/revised PY - 2020/04/21/accepted PY - 2020/5/15/pubmed PY - 2020/5/15/medline PY - 2020/5/15/entrez KW - Drugs KW - Neuroscience KW - Structural Biology SP - 101100 EP - 101100 JF - iScience JO - iScience VL - 23 IS - 5 N2 - Drug-resistant epileptic encephalopathies of infancy have been associated with KCNT1 gain-of-function mutations, which increase the activity of KNa1.1 sodium-activated potassium channels. Pharmacological inhibition of hyperactive KNa1.1 channels by quinidine has been proposed as a stratified treatment, but mostly this has not been successful, being linked to the low potency and lack of specificity of the drug. Here we describe the use of a previously determined cryo-electron microscopy-derived KNa1.1 structure and mutational analysis to identify how quinidine binds to the channel pore and, using computational methods, screened for compounds predicated to bind to this site. We describe six compounds that inhibited KNa1.1 channels with low- and sub-micromolar potencies, likely also through binding in the intracellular pore vestibule. In hERG inhibition and cytotoxicity assays, two compounds were ineffective. These may provide starting points for the development of new pharmacophores and could become tool compounds to study this channel further. SN - 2589-0042 UR - https://www.unboundmedicine.com/medline/citation/32408169/Structure-Based_Identification_and_Characterization_of_Inhibitors_of_the_Epilepsy-Associated_KNa1.1_(KCNT1)_Potassium_Channel L2 - https://linkinghub.elsevier.com/retrieve/pii/S2589-0042(20)30285-6 DB - PRIME DP - Unbound Medicine ER -
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