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Issue 5, 2011
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Probing the acceptor substrate binding site of Trypanosoma cruzi trans-sialidase with systematically modified substrates and glycoside libraries

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Abstract

Systematically modified octyl galactosides and octylN-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 α-(2→3)-sialylation of non-reducing terminal β-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.

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

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Publication details

The article was received on 04 Oct 2010, accepted on 22 Nov 2010 and first published on 21 Jan 2011


Article type: Paper
DOI: 10.1039/C0OB00826E
Org. Biomol. Chem., 2011,9, 1653-1660
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    Probing the acceptor substrate binding site of Trypanosoma cruzi trans-sialidase with systematically modified substrates and glycoside libraries

    J. A. Harrison, K. P. R. Kartha, E. J. L. Fournier, T. L. Lowary, C. Malet, U. J. Nilsson, O. Hindsgaul, S. Schenkman, J. H. Naismith and R. A. Field, Org. Biomol. Chem., 2011, 9, 1653
    DOI: 10.1039/C0OB00826E

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