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Title: Probing the acceptor substrate binding site of Trypanosoma cruzi trans-sialidase with systematically modified substrates and glycoside libraries
Authors: Harrison, Jennifer A.
Kartha, K. P. Ravindranathan
Fournier, Eric J. L.
Lowary, Todd L.
Malet, Carles
Nilsson, Ulf J.
Hindsgaul, Ole
Schenkman, Sergio [UNIFESP]
Naismith, James H.
Field, Robert A.
John Innes Ctr
Univ St Andrews
Natl Inst Pharmaceut Educ & Res
Univ Alberta
Lund Univ
Carlsberg Lab
Universidade Federal de São Paulo (UNIFESP)
Issue Date: 1-Jan-2011
Publisher: Royal Soc Chemistry
Citation: Organic & Biomolecular Chemistry. Cambridge: Royal Soc Chemistry, v. 9, n. 5, p. 1653-1660, 2011.
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.
ISSN: 1477-0520
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