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
Lee Kong Chian School of Medicine-Innovative CRO Explorer Collaborative Platform, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore.
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618.
Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2425494122. doi: 10.1073/pnas.2425494122. Epub 2025 Apr 28.
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 K3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K3.1 with an IC 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 K3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant K3.1 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. K3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which K3.1 has been experimentally confirmed as a therapeutic target.
1,4-二氢吡啶类药物具有公认的生物利用度和毒性特征，已被证明在治疗人类高血压、外周血管疾病和冠状动脉疾病方面有效。临床使用的每一种1,4-二氢吡啶都能阻断L型电压门控钙通道。我们现在报告，利用侧链活性的选择性优化（SOSA），开发了一类1,4-二氢吡啶，它们能选择性且强效地抑制中电导钙激活钾通道K3.1，这是一个已被验证的影响多个器官系统疾病的治疗靶点。其中一种1,4-二氢吡啶DHP-103，对K3.1的半数抑制浓度为6 nM，对钙通道和100多个其他分子靶点表现出极高的选择性。通过低温电子显微镜结合诱变和电生理学进行高分辨率结构测定，我们在K3.1通道孔充满水的中央腔内描绘了DHP-103的药物结合口袋，结合的药物直接阻碍离子渗透。DHP-103抑制了导致遗传性口形细胞增多症的功能获得性突变K3.1通道，表明其作为这种溶血性贫血治疗药物的潜在用途。在全球第二大致死原因急性缺血性中风的大鼠模型中，在概念验证研究中，缺血性损伤后12小时给予DHP-103可减少梗死体积，改善平衡木表现（本体感觉测量），并减少梗死区域活化小胶质细胞的数量。K3.1选择性1,4-二氢吡啶对许多疾病具有前景，在这些疾病中K3.1已被实验证实为治疗靶点。
