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

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

Author Harrison, Jennifer A. Google Scholar
Kartha, K. P. Ravindranathan Google Scholar
Fournier, Eric J. L. Google Scholar
Lowary, Todd L. Google Scholar
Malet, Carles Google Scholar
Nilsson, Ulf J. Google Scholar
Hindsgaul, Ole Google Scholar
Schenkman, Sergio Autor UNIFESP Google Scholar
Naismith, James H. Google Scholar
Field, Robert A. Google Scholar
Institution John Innes Ctr
Univ St Andrews
Natl Inst Pharmaceut Educ & Res
Univ Alberta
Lund Univ
Carlsberg Lab
Universidade Federal de São Paulo (UNIFESP)
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.
Language English
Sponsor BBSRC
Wellcome Trust
Grant number Wellcome Trust: 042472
Wellcome Trust: 040331
Date 2011-01-01
Published in Organic & Biomolecular Chemistry. Cambridge: Royal Soc Chemistry, v. 9, n. 5, p. 1653-1660, 2011.
ISSN 1477-0520 (Sherpa/Romeo, impact factor)
Publisher Royal Soc Chemistry
Extent 1653-1660
Origin http://dx.doi.org/10.1039/c0ob00826e
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000287368800049
URI http://repositorio.unifesp.br/handle/11600/33185

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