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Design of Glycosyltransferase Inhibitors : Targeting the Biosynthesis of Glycosaminoglycans by Phosphonate-Xyloside

Willén, Daniel LU ; Malmquist, Hanna ; Blasco, Pilar ; Björklund, Joachim LU ; Mastio, Roberto LU ; Manner, Sophie LU ; Widmalm, Göran ; Tykesson, Emil LU orcid and Ellervik, Ulf LU orcid (2025) In ACS Omega 10(47). p.57210-57218
Abstract

β-1,4-Galactosyltransferase 7 (β4GalT7) is a key enzyme in the biosynthesis of glycosaminoglycans (GAG) that transfers the first galactose unit to xylose in the linker region. Searching for new inhibitors of the GAG biosynthesis, we used saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy to evaluate the binding interactions between β4GalT7 and several pentosides in the presence of UDP donors. These investigations verified the glycosylation specificity of β4GalT7 and revealed that the naphthalene and the uridine moieties were significant contributors to the binding of the acceptor and the donor, respectively, while the galactose part was less important. Based on these findings, we set out to investigate... (More)

β-1,4-Galactosyltransferase 7 (β4GalT7) is a key enzyme in the biosynthesis of glycosaminoglycans (GAG) that transfers the first galactose unit to xylose in the linker region. Searching for new inhibitors of the GAG biosynthesis, we used saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy to evaluate the binding interactions between β4GalT7 and several pentosides in the presence of UDP donors. These investigations verified the glycosylation specificity of β4GalT7 and revealed that the naphthalene and the uridine moieties were significant contributors to the binding of the acceptor and the donor, respectively, while the galactose part was less important. Based on these findings, we set out to investigate conjugates of UDP and naphthoxylosides to function as transition state analogues. These compounds were synthesized using a one-pot procedure and tested as inhibitors in a β4GalT7 assay. Interestingly, one truncated analogue, a bisphosphonate-xyloside construct, showed a significant inhibition (IC50: 188 μM). These findings open for the design of a new class of inhibitors of the GAG biosynthesis.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
ACS Omega
volume
10
issue
47
pages
9 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:41358124
  • scopus:105023856656
ISSN
2470-1343
DOI
10.1021/acsomega.5c06840
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Authors. Published by American Chemical Society
id
c6c8680a-2708-4887-b315-22aaff1ecf93
date added to LUP
2025-12-15 08:12:05
date last changed
2026-01-12 11:10:46
@article{c6c8680a-2708-4887-b315-22aaff1ecf93,
  abstract     = {{<p>β-1,4-Galactosyltransferase 7 (β4GalT7) is a key enzyme in the biosynthesis of glycosaminoglycans (GAG) that transfers the first galactose unit to xylose in the linker region. Searching for new inhibitors of the GAG biosynthesis, we used saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy to evaluate the binding interactions between β4GalT7 and several pentosides in the presence of UDP donors. These investigations verified the glycosylation specificity of β4GalT7 and revealed that the naphthalene and the uridine moieties were significant contributors to the binding of the acceptor and the donor, respectively, while the galactose part was less important. Based on these findings, we set out to investigate conjugates of UDP and naphthoxylosides to function as transition state analogues. These compounds were synthesized using a one-pot procedure and tested as inhibitors in a β4GalT7 assay. Interestingly, one truncated analogue, a bisphosphonate-xyloside construct, showed a significant inhibition (IC<sub>50</sub>: 188 μM). These findings open for the design of a new class of inhibitors of the GAG biosynthesis.</p>}},
  author       = {{Willén, Daniel and Malmquist, Hanna and Blasco, Pilar and Björklund, Joachim and Mastio, Roberto and Manner, Sophie and Widmalm, Göran and Tykesson, Emil and Ellervik, Ulf}},
  issn         = {{2470-1343}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{47}},
  pages        = {{57210--57218}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Omega}},
  title        = {{Design of Glycosyltransferase Inhibitors : Targeting the Biosynthesis of Glycosaminoglycans by Phosphonate-Xyloside}},
  url          = {{http://dx.doi.org/10.1021/acsomega.5c06840}},
  doi          = {{10.1021/acsomega.5c06840}},
  volume       = {{10}},
  year         = {{2025}},
}