Hepatocyte Targeting and Intracellular Copper Chelation by a Thiol-Containing Glycocyclopeptide.
Metal overload plays an important role in several diseases or intoxications, like in Wilson's disease, a major genetic disorder of copper metab. in humans. To efficiently and selectively decrease copper concn. in the liver that is highly damaged, chelators should be targeted at the hepatocytes. In the present work, we synthesized a mol. able to both lower intracellular copper, namely Cu(I), and target hepatocytes, combining within the same structure a chelating unit and a carbohydrate recognition element. A cyclodecapeptide scaffold displaying a controlled conformation with two independent faces was chosen to introduce both units. One face displays a cluster of carbohydrates to ensure an efficient recognition of the asialoglycoprotein receptors, expressed on the surface of hepatocytes. The second face is devoted to metal ion complexation thanks to the thiolate functions of two cysteine side-chains. To obtain a chelator that is active only once inside the cells, the two thiol functions were oxidized in a disulfide bridge to afford the glycopeptide P3 (I). Two simple cyclodecapeptides modeling the reduced and complexing form of P3 in cells proved a high affinity for Cu(I) and a high selectivity with respect to Zn(II). As expected, P3 becomes an efficient Cu(I) chelator in the presence of glutathione that mimics the intracellular reducing environment. Finally, cellular uptake and ability to lower intracellular copper were demonstrated in hepatic cell lines, in particular in WIF-B9, making P3 a good candidate to fight copper overload in the liver. [on SciFinder(R)]
Références
- Titre
- Hepatocyte Targeting and Intracellular Copper Chelation by a Thiol-Containing Glycocyclopeptide.
- Type de publication
- Article de revue
- Année de publication
- 2011
- Auteurs
- Pujol, Anais M., Cuillel Martine, Renaudet Olivier, Lebrun Colette, Charbonnier Peggy, Cassio Doris, Gateau Christelle, Dumy Pascal, Mintz Elisabeth, and Delangle Pascale.
- Revue
- J. Am. Chem. Soc.
- Volume
- 133
- Pagination
- 286–296
- ISSN
- 0002-7863
Soumis le 12 avril 2018