Design and Structural Basis of Selective 1,4-dihydropyridine Inhibitors of the Calcium-activated Potassium Channel K_Ca3.1

Authors

Seow Theng Ong, Nanyang Technological University
Young-Woo Nam, Chapman UniversityFollow
Joshua A. Nasburg, University of California, Davis
Alena Ramanishka, Chapman University
Xuan Rui Ng, Nanyang Technological University
Zhong Zhuang, Nanyang Technological University
Stephanie Shee Min Goay, Nanyang Technological University
Hai M. Nguyen, University of California, Davis
Latika Singh, University of California, Davis
Vikrant Singh, University of California, Davis
Alicia Rivera, Beth Israel Deaconess Medical Center
M. Elaine Eyster, Penn State
Yang Xu, Stanford Linear Accelerator Center National Accelerator Laboratory
Seth L. Alper, Beth Israel Deaconess Medical Center
Heike Wulff, University of California, Davis
Miao Zhang, Chapman UniversityFollow
K. George Chandy, Nanyang Technological University, Singapore

Document Type

Article

Publication Date

4-28-2025

Abstract

The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery disease. Every 1,4-dihydropyridine in clinical use blocks L-type voltage-gated calcium channels. We now report our development, using selective optimization of a side activity (SOSA), of a class of 1,4-dihydropyridines that selectively and potently inhibit the intermediate-conductance calcium-activated K+ channel K_Ca3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K_Ca3.1 with an IC50 of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of >100 additional molecular targets. Using high-resolution structure determination by cryogenic electron microscopy together with mutagenesis and electrophysiology, we delineated the drug binding pocket for DHP-103 within the water-filled central cavity of the K_Ca3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant K_Ca3.1 channels that cause hereditary xerocytosis, suggesting its potential use as a therapeutic for this hemolytic anemia. In a rat model of acute ischemic stroke, the second leading cause of death worldwide, DHP-103 administered 12 h postischemic insult in proof-of-concept studies reduced infarct volume, improved balance beam performance (measure of proprioception) and decreased numbers of activated microglia in infarcted areas. K_Ca3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which K_Ca3.1 has been experimentally confirmed as a therapeutic target.

Comments

This article was originally published in Proceedings of the National Academy of Sciences, volume 122, issue 18, in 2025. https://doi.org/10.1073/pnas.2425494122

Recommended Citation

S.T. Ong,Y. Nam,J.A. Nasburg,A. Ramanishka,X.R. Ng,Z. Zhuang,S.S.M. Goay,H.M. Nguyen,L. Singh,V. Singh,A. Rivera,M.E. Eyster,Y. Xu,S.L. Alper,H. Wulff,M. Zhang,& K.G. Chandy, Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel K_Ca3.1, Proc. Natl. Acad. Sci. U.S.A. 122 (18) e2425494122, https://doi.org/10.1073/pnas.2425494122 (2025).

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The authors

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.