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

Jennifer A. Harrison, K. P.Ravindranathan Kartha, Eric J.L. Fournier, Todd L. Lowary, Carles Malet, Ulf J. Nilsson, Ole Hindsgaul, Sergio Schenkman, James H. Naismith, Robert A. Field

Research output: Indexed journal article Articlepeer-review

29 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1653-1660
Number of pages8
JournalOrganic and Biomolecular Chemistry
Volume9
Issue number5
DOIs
Publication statusPublished - 1 Mar 2011
Externally publishedYes

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