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Inhibition of heat-stable toxin–induced intestinal salt and water secretion by a novel class of guanylyl cyclase C inhibitors

(2015) JOURNAL OF INFECTIOUS DISEASES. 212(11). p.1806-1815
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Abstract
Background. Many enterotoxigenic Escherichia coli strains produce the heat-stable toxin, STa, which, by activa- tion of the intestinal receptor-enzyme guanylyl cyclase (GC) C, triggers an acute, watery diarrhea. We set out to identify GCC inhibitors that may be of benefit for the treatment of infectious diarrheal disease. Methods. Compounds that inhibit STa-induced cyclic guanosine 3′,5′-monophosphate (cGMP) production were selected by performing cyclase assays on cells and membranes containing GCC, or the related GCA. The effect of leads on STa/GCC-dependent activation of the cystic fibrosis transmembrane conductance regulator anion chan- nel was investigated in T84 cells, and in porcine and human intestinal tissue. Their effect on STa-provoked fluid transport was assessed in ligated intestinal loops in piglets. Results. Four N-2-(propylamino)-6-phenylpyrimidin-4-one–substituted piperidines were shown to inhibit GCC-mediated cellular cGMP production. The half maximal inhibitory concentrations were ≤5 × 10−7 mol/L, whereas they were >10 times higher for GCA. In T84 monolayers, these leads blocked STa/GCC-dependent, but not forskolin/adenylyl cyclase-dependent, cystic fibrosis transmembrane conductance regulator activity. GCC inhi- bition reduced STa-provoked anion secretion in pig jejunal tissue, and fluid retention and cGMP levels in STa- exposed loops. These GCC inhibitors blocked STa-provoked anion secretion in rectal biopsy specimens. Conclusions. We have identified a novel class of GCC inhibitors that may form the basis for development of future therapeutics for (infectious) diarrheal disease.
Keywords
enterotoxigenic E. coli (ETEC), CFTR, secretory diarrhea, guanylyl cyclase C, ADENINE-NUCLEOTIDES, CYSTIC-FIBROSIS, CELL-LINE, ENTEROTOXIN, DIARRHEA, ACTIVATION, TRANSPORT, MECHANISM, ADENYLYL, RECEPTOR

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MLA
Bijvelds, Marcel JC, et al. “Inhibition of Heat-Stable Toxin–Induced Intestinal Salt and Water Secretion by a Novel Class of Guanylyl Cyclase C Inhibitors.” JOURNAL OF INFECTIOUS DISEASES, vol. 212, no. 11, 2015, pp. 1806–15, doi:10.1093/infdis/jiv300.
APA
Bijvelds, M. J., Loos, M., Bronsveld, I., Hellemans, A., Bongartz, J.-P., Ver Donck, L., … De Maeyer, J. H. (2015). Inhibition of heat-stable toxin–induced intestinal salt and water secretion by a novel class of guanylyl cyclase C inhibitors. JOURNAL OF INFECTIOUS DISEASES, 212(11), 1806–1815. https://doi.org/10.1093/infdis/jiv300
Chicago author-date
Bijvelds, Marcel JC, Michaela Loos, Inez Bronsveld, Ann Hellemans, Jean-Pierre Bongartz, Luc Ver Donck, Eric Cox, Hugo R de Jonge, Jan AJ Schuurkes, and Joris H De Maeyer. 2015. “Inhibition of Heat-Stable Toxin–Induced Intestinal Salt and Water Secretion by a Novel Class of Guanylyl Cyclase C Inhibitors.” JOURNAL OF INFECTIOUS DISEASES 212 (11): 1806–15. https://doi.org/10.1093/infdis/jiv300.
Chicago author-date (all authors)
Bijvelds, Marcel JC, Michaela Loos, Inez Bronsveld, Ann Hellemans, Jean-Pierre Bongartz, Luc Ver Donck, Eric Cox, Hugo R de Jonge, Jan AJ Schuurkes, and Joris H De Maeyer. 2015. “Inhibition of Heat-Stable Toxin–Induced Intestinal Salt and Water Secretion by a Novel Class of Guanylyl Cyclase C Inhibitors.” JOURNAL OF INFECTIOUS DISEASES 212 (11): 1806–1815. doi:10.1093/infdis/jiv300.
Vancouver
1.
Bijvelds MJ, Loos M, Bronsveld I, Hellemans A, Bongartz J-P, Ver Donck L, et al. Inhibition of heat-stable toxin–induced intestinal salt and water secretion by a novel class of guanylyl cyclase C inhibitors. JOURNAL OF INFECTIOUS DISEASES. 2015;212(11):1806–15.
IEEE
[1]
M. J. Bijvelds et al., “Inhibition of heat-stable toxin–induced intestinal salt and water secretion by a novel class of guanylyl cyclase C inhibitors,” JOURNAL OF INFECTIOUS DISEASES, vol. 212, no. 11, pp. 1806–1815, 2015.
@article{7067298,
  abstract     = {{Background. Many enterotoxigenic Escherichia coli strains produce the heat-stable toxin, STa, which, by activa- tion of the intestinal receptor-enzyme guanylyl cyclase (GC) C, triggers an acute, watery diarrhea. We set out to identify GCC inhibitors that may be of benefit for the treatment of infectious diarrheal disease.
Methods. Compounds that inhibit STa-induced cyclic guanosine 3′,5′-monophosphate (cGMP) production were selected by performing cyclase assays on cells and membranes containing GCC, or the related GCA. The effect of leads on STa/GCC-dependent activation of the cystic fibrosis transmembrane conductance regulator anion chan- nel was investigated in T84 cells, and in porcine and human intestinal tissue. Their effect on STa-provoked fluid transport was assessed in ligated intestinal loops in piglets.
Results. Four N-2-(propylamino)-6-phenylpyrimidin-4-one–substituted piperidines were shown to inhibit GCC-mediated cellular cGMP production. The half maximal inhibitory concentrations were ≤5 × 10−7 mol/L, whereas they were >10 times higher for GCA. In T84 monolayers, these leads blocked STa/GCC-dependent, but not forskolin/adenylyl cyclase-dependent, cystic fibrosis transmembrane conductance regulator activity. GCC inhi- bition reduced STa-provoked anion secretion in pig jejunal tissue, and fluid retention and cGMP levels in STa- exposed loops. These GCC inhibitors blocked STa-provoked anion secretion in rectal biopsy specimens.
Conclusions. We have identified a novel class of GCC inhibitors that may form the basis for development of future therapeutics for (infectious) diarrheal disease.}},
  author       = {{Bijvelds, Marcel JC and Loos, Michaela and Bronsveld, Inez and Hellemans, Ann and Bongartz, Jean-Pierre and Ver Donck, Luc and Cox, Eric and de Jonge, Hugo R and Schuurkes, Jan AJ and De Maeyer, Joris H}},
  issn         = {{0022-1899}},
  journal      = {{JOURNAL OF INFECTIOUS DISEASES}},
  keywords     = {{enterotoxigenic E. coli (ETEC),CFTR,secretory diarrhea,guanylyl cyclase C,ADENINE-NUCLEOTIDES,CYSTIC-FIBROSIS,CELL-LINE,ENTEROTOXIN,DIARRHEA,ACTIVATION,TRANSPORT,MECHANISM,ADENYLYL,RECEPTOR}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{1806--1815}},
  title        = {{Inhibition of heat-stable toxin–induced intestinal salt and water secretion by a novel class of guanylyl cyclase C inhibitors}},
  url          = {{http://doi.org/10.1093/infdis/jiv300}},
  volume       = {{212}},
  year         = {{2015}},
}

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