# High-throughput screening identifies a trafficking corrector for long QT syndrome–associated KCNQ1 variants

## TL;DR

A new drug was found to correct a genetic defect in a potassium channel linked to a dangerous heart condition called long QT syndrome.

## Contribution

The first small molecule that corrects trafficking defects in KCNQ1 variants associated with long QT syndrome was identified.

## Key findings

- VU0494372 increases cell surface levels and trafficking efficiency of KCNQ1 and LQTS-associated variants.
- VU0494372 increases IKs current in cells expressing WT KCNQ1 and the LQTS variant V207M.
- The drug does not affect KCNQ1 transcription, degradation, or thermal stability but enhances its cell surface delivery.

## Abstract

Congenital long QT syndrome (LQTS) promotes risk for life-threatening cardiac arrhythmia and sudden death in children and young adults. Pathogenic variants in the voltage-gated potassium channel KCNQ1 are the most frequently discovered genetic cause. Most LQTS-associated KCNQ1 variants cause loss of function secondary to impaired trafficking of the channel to the plasma membrane. There are currently no therapeutic approaches that address this underlying molecular defect. Using a high-throughput screening paradigm, we identified VU0494372, a small molecule that increases total and cell surface levels and trafficking efficiency of WT KCNQ1 as well as three LQTS-associated variants. Additionally, 16-hour treatment of cells with VU0494372 increased IKs (KCNQ1-KCNE1 current) for WT KCNQ1 and the LQTS-associated variant V207M in cells coexpressing KCNE1. VU0494372 had no impact on KCNQ1 transcription, degradation, or thermal stability, and increased the rate of KCNQ1 reaching the cell surface. We identified a potential direct interaction site with KCNQ1 at or near the binding site of the KCNQ1 potentiator ML277. Together, these findings demonstrate that small molecules can increase the expression levels and cell surface trafficking efficiency of KCNQ1 and introduce a potential new pharmacological approach for treating LQTS.

We discovered and investigated the first trafficking corrector for KCNQ1 mutations that cause congenital long QT syndrome (LQTS), a life-threatening cardiac arrhythmia.