Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel K <sub>Ca</sub> 3.1
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 Ca 3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K Ca 3.1 with an IC 50 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 Ca 3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant K Ca 3.1 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 Ca 3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which K Ca 3.1 has been experimentally confirmed as a therapeutic target.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Seow Theng Ong
Lee Kong Chian School of Medicine-Innovative CRO Explorer Collaborative Platform, Lee Kong Chian School of Medicine, Nanyang Technological University
Young-Woo Nam
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy
Joshua A. Nasburg
Department of Pharmacology, School of Medicine, University of California
Alena Ramanishka
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy
Xuan Rui Ng
Lee Kong Chian School of Medicine-Innovative CRO Explorer Collaborative Platform, Lee Kong Chian School of Medicine, Nanyang Technological University
Zhong Zhuang
Lee Kong Chian School of Medicine-Innovative CRO Explorer Collaborative Platform, Lee Kong Chian School of Medicine, Nanyang Technological University
Stephanie Shee Min Goay
Lee Kong Chian School of Medicine-Innovative CRO Explorer Collaborative Platform, Lee Kong Chian School of Medicine, Nanyang Technological University
Hai M. Nguyen
Department of Pharmacology, School of Medicine, University of California
Latika Singh
Department of Pharmacology, School of Medicine, University of California
Vikrant Singh
Department of Pharmacology, School of Medicine, University of California
Alicia Rivera
Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center
M. Elaine Eyster
Division of Blood and Vascular Disorders, Department of Medicine, Penn State College of Medicine, Milton S. Hershey Medical Center
Yang Xu
Seth L. Alper
Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center
Heike Wulff
Department of Pharmacology, School of Medicine, University of California
Miao Zhang
State Key Laboratory of Advanced Materials for Intelligent Sensing, Key Laboratory of Organic Integrated Circuits, Ministry of Education & Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Department of Chemistry, School of Science
K. George Chandy
Lee Kong Chian School of Medicine-Innovative CRO Explorer Collaborative Platform, Lee Kong Chian School of Medicine, Nanyang Technological University