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Inhibition of Dermatan Sulfate Epimerase 1 by Substituted Glucuronic Acids

Mastio, Roberto LU ; Zuleta Sjögren, Isolde ; Dahlquist, John ; Sundin, Anders LU ; Westergren-Thorsson, Gunilla LU orcid ; Manner, Sophie LU ; Tykesson, Emil LU orcid ; Malmström, Anders LU orcid and Ellervik, Ulf LU orcid (2026) In ACS Omega 11(9). p.14719-14728
Abstract

Dermatan sulfate epimerase 1 (DS-epi1) is a key enzyme in the biosynthesis of the glycosaminoglycan chondroitin sulfate/dermatan sulfate, catalyzing the conversion of glucuronic acid to iduronic acid at the polymer level. Chondroitin sulfate/dermatan sulfate chains are found on at least 32 proteoglycans, many of which are implicated in human diseases and syndromes, as well as in both malignant and normal cell development. DS-epi1 therefore represents a promising target for drug development, and recent structural studies have provided insights into its active site and catalytic mechanism. Here, we report the synthesis and biological evaluation of inhibitors based on 1,4-disubstituted glucuronic acids. These compounds were synthesized... (More)

Dermatan sulfate epimerase 1 (DS-epi1) is a key enzyme in the biosynthesis of the glycosaminoglycan chondroitin sulfate/dermatan sulfate, catalyzing the conversion of glucuronic acid to iduronic acid at the polymer level. Chondroitin sulfate/dermatan sulfate chains are found on at least 32 proteoglycans, many of which are implicated in human diseases and syndromes, as well as in both malignant and normal cell development. DS-epi1 therefore represents a promising target for drug development, and recent structural studies have provided insights into its active site and catalytic mechanism. Here, we report the synthesis and biological evaluation of inhibitors based on 1,4-disubstituted glucuronic acids. These compounds were synthesized from glucose through a divergent approach, yielding 19 derivatives that were tested in a functional assay. To explore the importance of the carboxylic acid moiety, we also tested the methyl ester analog and the analogous xylose derivative. The most potent compound exhibited an IC
50 of 42 ± 4 μM. Molecular dynamics simulations showed a strong interaction with the active site of DS-epi1.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
ACS Omega
volume
11
issue
9
pages
10 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:105032219525
  • pmid:41835542
  • pmid:41835542
ISSN
2470-1343
DOI
10.1021/acsomega.5c10686
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2026 The Authors. Published by American Chemical Society
id
bb2ed520-8860-4046-b41a-d68364d87af6
date added to LUP
2026-03-22 21:16:27
date last changed
2026-03-24 11:48:48
@article{bb2ed520-8860-4046-b41a-d68364d87af6,
  abstract     = {{<p>Dermatan sulfate epimerase 1 (DS-epi1) is a key enzyme in the biosynthesis of the glycosaminoglycan chondroitin sulfate/dermatan sulfate, catalyzing the conversion of glucuronic acid to iduronic acid at the polymer level. Chondroitin sulfate/dermatan sulfate chains are found on at least 32 proteoglycans, many of which are implicated in human diseases and syndromes, as well as in both malignant and normal cell development. DS-epi1 therefore represents a promising target for drug development, and recent structural studies have provided insights into its active site and catalytic mechanism. Here, we report the synthesis and biological evaluation of inhibitors based on 1,4-disubstituted glucuronic acids. These compounds were synthesized from glucose through a divergent approach, yielding 19 derivatives that were tested in a functional assay. To explore the importance of the carboxylic acid moiety, we also tested the methyl ester analog and the analogous xylose derivative. The most potent compound exhibited an IC <br>
 50 of 42 ± 4 μM. Molecular dynamics simulations showed a strong interaction with the active site of DS-epi1.<br>
 </p>}},
  author       = {{Mastio, Roberto and Zuleta Sjögren, Isolde and Dahlquist, John and Sundin, Anders and Westergren-Thorsson, Gunilla and Manner, Sophie and Tykesson, Emil and Malmström, Anders and Ellervik, Ulf}},
  issn         = {{2470-1343}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{9}},
  pages        = {{14719--14728}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Omega}},
  title        = {{Inhibition of Dermatan Sulfate Epimerase 1 by Substituted Glucuronic Acids}},
  url          = {{http://dx.doi.org/10.1021/acsomega.5c10686}},
  doi          = {{10.1021/acsomega.5c10686}},
  volume       = {{11}},
  year         = {{2026}},
}