2098-LB: Identification and Structural Elucidation of a Novel KATP Channel Modulator Demonstrating Dual Pharmacochaperone and Inhibitory Actions

Introduction & Objectives: Pancreatic K_ATP channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the K_ATP opener diazoxide, the mainstay medical therapy for CHI. Current clinically used K_ATP channel inhibitors have been shown to act as pharmacochaperones (PCs) and restore surface expression of trafficking mutants; however, their therapeutic utility for CHI is hindered by irreversible binding, which limits the functional recovery of rescued channels. Cryo-electron microscopy (Cryo-EM) structures of K_ATP channels bound to inhibitors offer prospects of structure-guided drug discovery for CHI treatment. The study aims to identify K_ATP channel PCs with reversible inhibitory effects to enable functional recovery of rescued channels and to elucidate the reversible PC mechanism using cryo-EM.

Methods: Functional and biochemical studies were used to identify a novel compound with PC effects and pancreatic K_ATP isoform specificity. Single-particle cryo-EM and mutagenesis studies were used to elucidate the mechanisms of the PC and inhibitory actions of this compound.

Results: We identified a novel compound exhibiting robust chaperoning effects on K_ATP channel trafficking mutations and reversible inhibition of K_ATP channel function. This PC displayed pancreatic K_ATP channel specificity and distinct binding features compared to inhibitors with persistent effects.

Conclusion: Our findings unveil a novel K_ATP PC enabling functional recovery of rescued channels, holding promise for novel therapeutics in CHI caused by K_ATP trafficking defects.