title: Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis.
abstract: Pendrin (SLC26A4) is a Cl(-)/anion exchanger expressed in the epithelium of inflamed airways where it is thought to facilitate Cl(-) absorption and HCO3 (-) secretion. Studies using pendrin knockout mice and airway epithelial cells from hearing-impaired subjects with pendrin loss of function suggest involvement of pendrin in inflammatory lung diseases, including cystic fibrosis (CF), perhaps by regulation of airway surface liquid (ASL) volume. Here we identified small-molecule pendrin inhibitors and demonstrated their efficacy in increasing ASL volume. A cell-based, functional high-throughput screen of ∼36,000 synthetic small molecules produced 3 chemical classes of inhibitors of human pendrin. After structure-activity studies, tetrahydropyrazolopyridine and pyrazolothiophenesulfonamide compounds reversibly inhibited pendrin-facilitated Cl(-) exchange with SCN(-), I(-), NO3 (-), and HCO3 (-) with drug concentration causing 50% inhibition down to ∼2.5 μM. In well-differentiated primary cultures of human airway epithelial cells from non-CF and CF subjects, treatment with IL-13, which causes inflammation with strong pendrin up-regulation, strongly increased Cl(-)/HCO3 (-) exchange and the increase was blocked by pendrin inhibition. Pendrin inhibition significantly increased ASL depth (by ∼8 μm) in IL-13-treated non-CF and CF cells but not in untreated cells. These studies implicate the involvement of pendrin-facilitated Cl(-)/HCO3 (-) in the regulation of ASL volume and suggest the utility of pendrin inhibitors in inflammatory lung diseases, including CF.-Haggie, P. M., Phuan, P.-W., Tan, J.-A., Zlock, L., Finkbeiner, W. E., Verkman, A. S. Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis.
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA; Department of Physiology, University of California, San Francisco, San Francisco, California, USA; and.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haggie
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA; Department of Physiology, University of California, San Francisco, San Francisco, California, USA; and.
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA; Department of Physiology, University of California, San Francisco, San Francisco, California, USA; and.
authors.forename: Joseph-Anthony
authors.initials: JA
authors.lastname: Tan
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California, USA;
authors.forename: Lorna
authors.initials: L
authors.lastname: Zlock
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California, USA;
authors.forename: Walter E
authors.initials: WE
authors.lastname: Finkbeiner
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA; Department of Physiology, University of California, San Francisco, San Francisco, California, USA; and alan.verkman@ucsf.edu.
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D027963:Chloride-Bicarbonate Antiporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003550:Cystic Fibrosis / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D000076988:Sulfate Transporters; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D027963:Chloride-Bicarbonate Antiporters; D018793:Interleukin-13; D026901:Membrane Transport Proteins; D011725:Pyridines; C085609:SLC26A4 protein, human; C494615:Slc26A4 protein, rat; D000076988:Sulfate Transporters; D013449:Sulfonamides
keywords: ASL; drug discovery; high-throughput screening; inflammatory airway disease