title: Evaluation of carbohydrate-cysteamine thiazolidines as pro-drugs for the treatment of cystinosis.
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.
authors.affiliation: Department of Pediatric Nephrology and Growth and Regeneration, University Hospitals Leuven and University of Leuven, UZ Herestraat 49, Box 817, 3000 Leuven, Belgium.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Ramazani
authors.affiliation: Department of Pediatric Nephrology and Growth and Regeneration, University Hospitals Leuven and University of Leuven, UZ Herestraat 49, Box 817, 3000 Leuven, Belgium.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Levtchenko
authors.affiliation: Department of Pediatric Nephrology, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands.
authors.forename: Lambertus
authors.initials: L
authors.lastname: Van Den Heuvel
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, University of Leuven, O&N II Herestraat 49, Box 923, 3000 Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Van Schepdael
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, University of Leuven, O&N II Herestraat 49, Box 923, 3000 Leuven, Belgium.
authors.forename: Prasanta
authors.initials: P
authors.lastname: Paul
authors.affiliation: Department of Pediatric Nephrology and Growth and Regeneration, University Hospitals Leuven and University of Leuven, UZ Herestraat 49, Box 817, 3000 Leuven, Belgium.
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Ivanova
authors.affiliation: Laboratory of Metabolomics and Proteomics Bambino Gesu Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pastore
authors.affiliation: Agricultural Research Service, U.S. Department of Agriculture, National Center for Agricultural Utilization Research, Peoria, IL 61604, USA.
authors.forename: Trina M
authors.initials: TM
authors.lastname: Hartman
authors.affiliation: Agricultural Research Service, U.S. Department of Agriculture, National Center for Agricultural Utilization Research, Peoria, IL 61604, USA. Electronic address: neil.price@ars.usda.gov.
authors.forename: Neil P J
authors.initials: NPJ
authors.lastname: Price
mesh_terms: D001089:Arabinose / Q000737:chemistry; D001711:Biotransformation; D003543:Cysteamine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D065104:Cystine Depleting Agents / Q000378:metabolism / Q000494:pharmacology; D003554:Cystinosis / Q000378:metabolism / Q000473:pathology; D015195:Drug Design; D005110:Extracellular Space / Q000737:chemistry* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D007785:Lactose / Q000737:chemistry; D015394:Molecular Structure; D061251:Primary Cell Culture; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D012266:Ribose / Q000737:chemistry; D013440:Sulfides / Q000378:metabolism; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D065104:Cystine Depleting Agents; D011355:Prodrugs; D013440:Sulfides; D053778:Thiazolidines; D003543:Cysteamine; D012266:Ribose; D001089:Arabinose; D005947:Glucose; D007785:Lactose; C004784:dimethyl sulfide
keywords: Carbohydrate-cysteamine thiazolidines; Cysteamine; Cystinosis; Halitosis; Pro-drug