Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel KCa3.1

• 成果类型: Article
• 署名作者: Ong, Seow Theng; Nam, Young - Woo; Nasburg, Joshua A.; Ramanishka, Alena; Ng, Xuan Rui; Zhuang, Zhong; Goay, Stephanie Shee Min; Nguyen, Hai M.; Singh, Latika; Singh, Vikrant; Rivera, Alicia; Eyster, M. Elaine; Xu, Yang; Alper, Seth L.; Wulff, Heike; Zhang, Miao; Chandy, K. George
• 署名单位: Nanyang Technological University; Chapman University System; Chapman University; University of California System; University of California Davis; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard Medical School; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11737
• DOI: 10.1073/pnas.2425494122
• 发表日期: 2025-05-06
• 关键词: ca2+-activated k+ channel; t-cell-activation; gardos channel; kcnn4; mutations; mechanism; potent; dehydration; senicapoc; ikca1

摘要

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 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(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.