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

Yasaman Ramazani, Elena N. Levtchenko, Lambertus P. van Den Heuvel, Ann Van Schepdael, Prasanta Paul, Ekaterina A. Ivanova, Anna Pastore, Trina M. Hartman, Neil P J Price

Research output: Contribution to journalArticlepeer-review

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 analogs 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 extracellularly 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.

Original languageEnglish
Pages (from-to)9-15
Number of pages7
JournalCarbohydrate Research
Volume439
DOIs
Publication statusPublished - Dec 18 2016

Keywords

  • Arabinose
  • Biotransformation
  • Cysteamine
  • Cystine Depleting Agents
  • Cystinosis
  • Drug Design
  • Extracellular Space
  • Fibroblasts
  • Glucose
  • Humans
  • Hydrolysis
  • Lactose
  • Molecular Structure
  • Primary Cell Culture
  • Prodrugs
  • Ribose
  • Sulfides
  • Thiazolidines
  • Journal Article

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