CARLEO, GIUSY (2025) FUNCTIONAL CHARACTERIZATION OF NOVEL Kv7 POTASSIUM CHANNEL MODULATORS DISCOVERED VIA DRUG REPURPOSING AND IN SILICO STRATEGIES. [Tesi di dottorato]

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Abstract

Kv7 potassium channels, encoded by the KCNQ gene family, play a fundamental role in neuronal excitability and are implicated in various neurological disorders, including epilepsy and developmental encephalopathies. This study aims to identify and characterize novel Kv7 modulators using a combined approach of drug repurposing and computational modeling. High-throughput screening (HTS) of a repurposing library led to the discovery of promising Kv7 activators, which were further evaluated through electrophysiological techniques, including manual patch-clamp and multi-electrode arrays. The most effective compound, C4, was examined for its selectivity, binding site, and functional effects on iPSC-derived cortical excitatory neurons and preclinical seizure models. Additionally, in silico-guided synthesis was employed to design CPRET-106, a novel Kv7.2 modulator, which was assessed for its effects on wild-type and gain-of-function mutant channels. The findings contribute to the pharmacological understanding of Kv7 channels and highlight potential therapeutic candidates for epilepsy and related disorders.

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