Key result
Kv3.1 inhibitor VU426 exhibits up to ~5-fold enhanced potency for pathogenic gain-of-function mutants versus wild-type.
Why the study?
Progress toward small-molecule Kv3.1 inhibitors has been limited, despite Kv3.1 gain-of-function mutations being implicated in neurological disease.
The discovery of VU426 as a state-dependent Kv3.1 inhibitor demonstrates a pharmacological strategy for targeting clinically identified pathogenic gain-of-function variants.
Novel Kv3.1 inhibitors may counter gain-of-function hyperexcitability; leaves open therapeutic translation pending disease-model validation.
Kv3.1 voltage-gated potassium channels play a critical role in regulating neuronal excitability, and dysregulation driven by gain of function (GoF) mutations has been implicated in neurological disease. While Kv3.1 potentiators have been at the forefront of drug development as a means to enhance neuronal firing, progress towards small-molecule Kv3.1 inhibitors has been limited. Here we address this gap with the discovery of novel and structurally diverse Kv3.1 channel inhibitors identified through a high throughput screening (HTS) of over 50,000 compounds. Among these, VU426 emerged as the most potent compound with an IC 50 of 4.3 μM. VU426 induces pronounced, state dependent inhibition of outward K+ current with sustained depolarization indicating stabilization of an inactivated channel conformation accessed from the open state. Functional characterization of four GoF mutations (V425M, M430I, V432M, V434L) in S6 pore lining domain demonstrated that VU426 exhibits 1.5- to 5-fold enhanced potency toward pathogenic GoF Kv3.1 mutants relative to wild type channels. Automated patch-clamp electrophysiological studies revealed V432M and V434L mutations embedded deep in S6 domain had the greatest sensitivity to VU426. Despite its potency, VU426 exhibited limited selectivity for Kv3.1 over related Kv channels. Together, these findings identify novel Kv3.1 inhibitors and highlight a pharmacological strategy for targeting clinically identified pathogenic variants.
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Chandrappa et al. (2026) studied Neurological disease (Kv3.1 gain-of-function mutations). VU426 (VU0521426) vs. Wild type channels was evaluated on Potency toward pathogenic GoF Kv3.1 mutants relative to wild type channels (1.5- to 5-fold enhanced potency). The novel Kv3.1 channel inhibitor VU426 exhibited 1.5- to 5-fold enhanced potency toward pathogenic gain-of-function mutants relative to wild-type channels.
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