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Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts

Maccarana, Marco LU ; Tykesson, Emil LU orcid ; Pera, Edgar M. LU ; Gouignard, Nadège LU ; Fang, Jianping ; Malmström, Anders LU orcid ; Ghiselli, Giancarlo LU and Li, Jin Ping (2021) In Glycobiology 31(10). p.1319-1329
Abstract

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... (More)

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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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
chondroitin dermatan sulfate, ebselen, epimerases, mucopolysaccharidosis type I, substrate reduction therapy
in
Glycobiology
volume
31
issue
10
pages
11 pages
publisher
Oxford University Press
external identifiers
  • scopus:85121130273
  • pmid:34192316
ISSN
0959-6658
DOI
10.1093/glycob/cwab066
language
English
LU publication?
yes
id
ec98dc64-fe51-4530-be67-073763101673
date added to LUP
2022-02-03 11:56:05
date last changed
2024-06-18 06:18:31
@article{ec98dc64-fe51-4530-be67-073763101673,
  abstract     = {{<p>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. </p>}},
  author       = {{Maccarana, Marco and Tykesson, Emil and Pera, Edgar M. and Gouignard, Nadège and Fang, Jianping and Malmström, Anders and Ghiselli, Giancarlo and Li, Jin Ping}},
  issn         = {{0959-6658}},
  keywords     = {{chondroitin dermatan sulfate; ebselen; epimerases; mucopolysaccharidosis type I; substrate reduction therapy}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{10}},
  pages        = {{1319--1329}},
  publisher    = {{Oxford University Press}},
  series       = {{Glycobiology}},
  title        = {{Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts}},
  url          = {{http://dx.doi.org/10.1093/glycob/cwab066}},
  doi          = {{10.1093/glycob/cwab066}},
  volume       = {{31}},
  year         = {{2021}},
}