Journal
FASEB JOURNAL
Volume 19, Issue 13, Pages 130-+Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.05-4818fje
Keywords
diarrhea; cystic fibrosis; chloride channel; drug discovery
Categories
Funding
- NEI NIH HHS [EY-13574] Funding Source: Medline
- NHLBI NIH HHS [HL-73854] Funding Source: Medline
- NIAID NIH HHS [AI-062530] Funding Source: Medline
- NIBIB NIH HHS [EB-00415] Funding Source: Medline
- NIDDK NIH HHS [DK-43840, DK-72517, DK35124] Funding Source: Medline
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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-(2hydroxyethyl)]-glycine- 2-[(3,5-dibromo-2,4-dihydroxyphenyl) methylene] hydrazide. Compounds rapidly, fully and reversibly blocked CFTR-mediated chloride current with K-i of 2-8 mu M 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.
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