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TitleDesign and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel K3.1.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 18, Page e2425494122, Year 2025
Publish dateMay 6, 2025
AuthorsSeow Theng Ong / Young-Woo Nam / Joshua A Nasburg / Alena Ramanishka / Xuan Rui Ng / Zhong Zhuang / Stephanie Shee Min Goay / Hai M Nguyen / Latika Singh / Vikrant Singh / Alicia Rivera / M Elaine Eyster / Yang Xu / Seth L Alper / Heike Wulff / Miao Zhang / K George Chandy /
PubMed AbstractThe 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery ...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.
External linksProc Natl Acad Sci U S A / PubMed:40294255 / PubMed Central
MethodsEM (single particle)
Resolution3.5 Å
Structure data

47930

9ed1

EMDB-47930, PDB-9ed1:
Cryo-EM structure of the human KCa3.1/calmodulin channel in complex with Ca2+ and 1,4-dihydropyridine (DHP-103)
Method: EM (single particle) / Resolution: 3.5 Å

Chemicals

ChemComp-K:
Unknown entry

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
KeywordsTRANSPORT PROTEIN / Ion channel / Membrane protein / Ca-binding protein

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