Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated K_Na1.1 (KCNT1) Potassium Channel.

ABSTRACT: Drug-resistant epileptic encephalopathies of infancy have been associated with KCNT1 gain-of-function mutations, which increase the activity of K_Na1.1 sodium-activated potassium channels. Pharmacological inhibition of hyperactive K_Na1.1 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 K_Na1.1 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 K_Na1.1 channels with low- and sub

SUBMITTER: Cole BA 

PROVIDER: S-EPMC7225746 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature