Evaluation of carbohydrate-cysteamine thiazolidines as pro-drugs for the treatment of cystinosis

Authors: RAMAZANI, YASAMAN - Leuven University Hospital; LEVTCHENKO, ELENA - Leuven University Hospital; VAN DEN HEUVEL, LAMBERTUS - Leuven University Hospital; PASTORE, ANNE - Ospedale Pediatrico Bambino Gesu; IVANOVA, EKATERINA - Leuven University Hospital; Hartman, Trina; Price, Neil

Submitted to: Carbohydrate Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/12/2016
Publication Date: 2/1/2017
Publication URL: https://handle.nal.usda.gov/10113/5602175
Citation: Ramazani, Y., Levtchenko, E.N., Van Den Heuvel, L., Van Schepdael, A., Prasanta, P., Ivanova, E.A., Pastore, A., Hartman, T.M., Price, N.P.J. 2017. Evaluation of carbohydrate-cysteamine thiazolidines as pro-drugs for the treatment of cystinosis. Carbohydrate Research. 439:9-15.

Interpretive Summary: Cystinosis is a rare metabolic disease in children that leads to an over accumulation of some sulfur amino acids in cells all through the body. How this occurs is still unknown. The most effective treatment for this since 1976 is the dietary use of cysteamine. However, the most common side effects of cysteamine are reported to be gastro-intestinal discomfort, halitosis and disagreeable sweat odor. These side effects and the frequency of administration can negatively influence the compliance of patients. There is therefore a great demand for new cysteamine preparations that can reduce the side effects and increase patients’ compliance. We report the preparation of non-odorous carbohydrate-cysteamine compounds, and their biological testing in patient-derived cystinotic fibroblast cells. Some of these compounds are almost as effective as cysteamine itself, and we therefore recommend further testing for these compounds.

Technical Abstract: Cystinosis is a genetic disorder caused by malfunction of cystinosin and is characterized by accumulation of cystine. Cysteamine, the medication used in cystinosis, causes halitosis resulting in poor patient compliance. Halitosis is mainly caused by the formation of dimethylsulfide as the final product in the cysteamine metabolism pathway. We have synthesized carbohydrate-cysteamine thiazolidines, and hypothesized that the hydrolytic breakdown of cysteamine-thiazolidines can result in free cysteamine being released in target organs. To examine our hypothesis, we tested these analogues in vitro in patient-derived fibroblasts. Cystinotic fibroblasts were treated with different concentrations of arabinose-cysteamine, glucose-cysteamine and maltose cysteamine. We demonstrated that the analogs break down into cysteamine extracelluarly and might therefore not be fully taken up by the cells under the form of the pro-drug. Potential modifications of the analogs that enable their intracellular rather than extracellular breakdown is necessary to pursue the potential of these analogs as pro-drugs.