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ResearchIn-Press PreviewCardiologyGenetics Open Access | 10.1172/jci.insight.201297

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

Katherine R. Clowes Moster,1 Carlos G. Vanoye,2 Ana C. Chang-Gonzalez,3 Ian M. Romaine,4 Katherine M. Stefanski,1 Mason C. Wilkinson,1 Joshua A. Bauer,1 Thomas P. Hasaka,4 Emily L. Days,4 Reshma R. Desai,2 Kathryn R. Butcher,1 Gary A. Sulikowski,5 Alex G. Waterson,5 Jens Meiler,3 Kaitlyn V. Ledwitch,3 Alfred L. George, Jr.,2 and Charles R. Sanders1

1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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1Department of Biochemistry, Vanderbilt University, Nashville, United States of America

2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Center for Structural Biology, Vanderbilt University, Nashville, United States of America

4Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States of America

5Department of Chemistry, Vanderbilt University, Nashville, United States of America

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Published January 8, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.201297.
Copyright © 2026, Clowes Moster et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 8, 2026 - Version history
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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 co-expressing 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.

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  • Version 1 (January 8, 2026): In-Press Preview
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