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Probing the acceptor substrate binding site of Trypanosoma cruzi trans-sialidase with systematically modified substrates and glycoside libraries

Harrison, Jennifer A.; Kartha, K. P. Ravindranathan; Fournier, Eric J. L.; Lowary, Todd L.; Malet, Carles; Nilsson, Ulf LU ; Hindsgaul, Ole; Schenkman, Sergio; Naismith, James H. and Field, Robert A. (2011) In Organic and Biomolecular Chemistry 9(5). p.1653-1660
Abstract
Systematically modified octyl galactosides and octyl N-acetyllactosamines were assessed as inhibitors of, and substrates for, T. cruzi trans-sialidase (TcTS) in the context of exploring its acceptor substrate binding site. These studies show that TcTS, which catalyses the alpha-(2 -> 3)-sialylation of non-reducing terminal beta-galactose residues, is largely intolerant of substitution of the galactose 2 and 4 positions whereas substitution of the galactose 6 position is well tolerated. Further studies show that even the addition of a bulky sugar residue (glucose, galactose) does not impact negatively on TcTS binding and turnover, which highlights the potential of 'internal' 6-substituted galactose residues to serve as TcTS acceptor... (More)
Systematically modified octyl galactosides and octyl N-acetyllactosamines were assessed as inhibitors of, and substrates for, T. cruzi trans-sialidase (TcTS) in the context of exploring its acceptor substrate binding site. These studies show that TcTS, which catalyses the alpha-(2 -> 3)-sialylation of non-reducing terminal beta-galactose residues, is largely intolerant of substitution of the galactose 2 and 4 positions whereas substitution of the galactose 6 position is well tolerated. Further studies show that even the addition of a bulky sugar residue (glucose, galactose) does not impact negatively on TcTS binding and turnover, which highlights the potential of 'internal' 6-substituted galactose residues to serve as TcTS acceptor substrates. Results from screening a 93-membered thiogalactoside library highlight a number of structural features (notably imidazoles and indoles) that are worthy of further investigation in the context of TcTS inhibitor development. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Organic and Biomolecular Chemistry
volume
9
issue
5
pages
1653 - 1660
publisher
Royal Society of Chemistry
external identifiers
  • wos:000287368800049
  • scopus:79951621284
ISSN
1477-0539
DOI
10.1039/c0ob00826e
language
English
LU publication?
yes
id
ea44a9f6-4af7-459f-af8e-97b1d4ee4162 (old id 1868923)
date added to LUP
2011-04-19 11:09:21
date last changed
2017-05-28 03:07:38
@article{ea44a9f6-4af7-459f-af8e-97b1d4ee4162,
  abstract     = {Systematically modified octyl galactosides and octyl N-acetyllactosamines were assessed as inhibitors of, and substrates for, T. cruzi trans-sialidase (TcTS) in the context of exploring its acceptor substrate binding site. These studies show that TcTS, which catalyses the alpha-(2 -> 3)-sialylation of non-reducing terminal beta-galactose residues, is largely intolerant of substitution of the galactose 2 and 4 positions whereas substitution of the galactose 6 position is well tolerated. Further studies show that even the addition of a bulky sugar residue (glucose, galactose) does not impact negatively on TcTS binding and turnover, which highlights the potential of 'internal' 6-substituted galactose residues to serve as TcTS acceptor substrates. Results from screening a 93-membered thiogalactoside library highlight a number of structural features (notably imidazoles and indoles) that are worthy of further investigation in the context of TcTS inhibitor development.},
  author       = {Harrison, Jennifer A. and Kartha, K. P. Ravindranathan and Fournier, Eric J. L. and Lowary, Todd L. and Malet, Carles and Nilsson, Ulf and Hindsgaul, Ole and Schenkman, Sergio and Naismith, James H. and Field, Robert A.},
  issn         = {1477-0539},
  language     = {eng},
  number       = {5},
  pages        = {1653--1660},
  publisher    = {Royal Society of Chemistry},
  series       = {Organic and Biomolecular Chemistry},
  title        = {Probing the acceptor substrate binding site of Trypanosoma cruzi trans-sialidase with systematically modified substrates and glycoside libraries},
  url          = {http://dx.doi.org/10.1039/c0ob00826e},
  volume       = {9},
  year         = {2011},
}