Journal
GLYCOBIOLOGY
Volume 31, Issue 10, Pages 1319-1329Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/glycob/cwab066
Keywords
chondroitin dermatan sulfate; ebselen; epimerases; mucopolysaccharidosis type I; substrate reduction therapy
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Funding
- Exploratory Pre-Seed Funding Novo Nordisk [23722]
- Swedish Research Council [2018-02503]
- O.E. and Edla Johansson's Scientific Foundation
- Director Albert Pahlsson's Foundation
- Swedish Childhood Cancer Foundation [PROJ11/101, NBCNSPDHEL12/012]
- Swedish Research Council [2018-02503] Funding Source: Swedish Research Council
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Ebselen was identified as a potent inhibitor of enzymes producing iduronic acid in CS/DS and HS, reducing the accumulation of CS/DS and promoting GAG degradation in MPS-I fibroblasts. While it failed to ameliorate the burden in MPS-I mice, the study suggests a potential for iduronic acid substrate reduction therapy for MPS-I patients.
Mucopolysaccharidosis type I (MPS-I) is a rare lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase, which removes iduronic acid in both chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) and thereby contributes to the catabolism of glycosaminoglycans (GAGs). To ameliorate this genetic defect, the patients are currently treated by enzyme replacement and bone marrow transplantation, which have a number of drawbacks. This study was designed to develop an alternative treatment by inhibition of iduronic acid formation. By screening the Prestwick drug library, we identified ebselen as a potent inhibitor of enzymes that produce iduronic acid in CS/DS and HS. Ebselen efficiently inhibited iduronic acid formation during CS/DS synthesis in cultured fibroblasts. Treatment of MPS-I fibroblasts with ebselen not only reduced accumulation of CS/DS but also promoted GAG degradation. In early Xenopus embryos, this drug phenocopied the effect of downregulation of DS-epimerase 1, the main enzyme responsible for iduronic production in CS/DS, suggesting that ebselen inhibits iduronic acid production in vivo. However, ebselen failed to ameliorate the CS/DS and GAG burden in MPS-I mice. Nevertheless, the results propose a potential of iduronic acid substrate reduction therapy for MPS-I patients.
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