Nanomolar CFTR Inhibition by Pore-Occluding Divalent Polyethylene Glycol-Malonic Acid Hydrazides

N. D. Sonawane, Dan Zhao, Olga Zegarra-Moran, Luis J V Galietta, A. S. Verkman

Research output: Contribution to journalArticle

Abstract

Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have potential application as antisecretory therapy in cholera. We synthesized mono- and divalent CFTR inhibitors consisting of a malonic acid hydrazide (MalH) coupled via a disulfonic stilbene linker to polyethylene glycols (PEGs; 0.2-100 kDa). IC50 values for CFTR inhibition were 10-15 μM for the monovalent MalH-PEGs, but substantially lower for divalent MalH-PEG-MalH compounds, decreasing from 1.5 to 0.3 μM with increasing PEG size and showing positive cooperativity. Whole-cell patch-clamp showed voltage-dependent CFTR block with inward rectification. Outside-out patch-clamp showed shortened single-channel openings, indicating CFTR pore block from the extracellular side. Luminally added MalH-PEG-MalH blocked by >90% cholera toxin-induced fluid secretion in mouse intestinal loops (IC50 ∼10 pmol/loop), and greatly reduced mortality in a suckling mouse cholera model. These conjugates may provide safe, inexpensive antisecretory therapy.

Original languageEnglish
Pages (from-to)718-728
Number of pages11
JournalChemistry and Biology
Volume15
Issue number7
DOIs
Publication statusPublished - Jul 21 2008

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Keywords

  • CELLBIO
  • CHEMBIO
  • SIGNALING

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Sonawane, N. D., Zhao, D., Zegarra-Moran, O., Galietta, L. J. V., & Verkman, A. S. (2008). Nanomolar CFTR Inhibition by Pore-Occluding Divalent Polyethylene Glycol-Malonic Acid Hydrazides. Chemistry and Biology, 15(7), 718-728. https://doi.org/10.1016/j.chembiol.2008.05.015