Luminally active, nonabsorbable CFTR inhibitors as potential therapy to reduce intestinal fluid loss in cholera

FASEB J. 2006 Jan;20(1):130-2. doi: 10.1096/fj.05-4818fje. Epub 2005 Nov 29.


Enterotoxin-mediated secretory diarrheas such as cholera involve chloride secretion by enterocytes into the intestinal lumen by the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. We previously identified glycine hydrazide CFTR blockers that by electrophysiological studies appeared to block the CFTR anion pore at its lumen-facing surface. Here, we synthesize highly water-soluble, nonabsorbable malondihydrazides by coupling 2,4-disulfobenzaldehyde, 4-sulfophenylisothiocyante, and polyethylene glycol (PEG) moieties to 2-naphthalenylamino-[(3,5-dibromo-2,4-dihydroxyphenyl) methylene] propanedioic acid dihydrazide, and aminoacethydrazides by coupling PEG to [(N-2-naphthalenyl)-2-(2-hydroxyethyl)]-glycine-2-[(3,5-dibromo-2,4-dihydroxyphenyl) methylene] hydrazide. Compounds rapidly, fully and reversibly blocked CFTR-mediated chloride current with Ki of 2-8 microM when added to the apical surface of epithelial cell monolayers. Compounds did not pass across Caco-2 monolayers, and were absorbed by <2%/hr in mouse intestine. Luminally added compounds blocked by >90% cholera toxin-induced fluid secretion in mouse intestinal loops, without inhibiting intestinal fluid absorption. These orally administered, nonabsorbable, nontoxic CFTR inhibitors may reduce intestinal fluid losses in cholera.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Cells, Cultured
  • Cholera / complications*
  • Cholera / drug therapy*
  • Cholera / physiopathology
  • Cholera Toxin / toxicity
  • Cystic Fibrosis Transmembrane Conductance Regulator / antagonists & inhibitors*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Dehydration / complications
  • Dehydration / drug therapy*
  • Dehydration / physiopathology
  • Diarrhea / complications
  • Diarrhea / drug therapy*
  • Diarrhea / physiopathology
  • Glycine / analogs & derivatives
  • Glycine / chemical synthesis
  • Glycine / pharmacology*
  • Glycine / therapeutic use*
  • Humans
  • Intestinal Absorption
  • Intestinal Mucosa / metabolism
  • Mice
  • Rats
  • Rats, Inbred F344
  • Thyroid Gland / cytology


  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Cholera Toxin
  • Glycine