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

På svenska

Author

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

Summary, in English

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.

Publishing year

2011

Language

English

Pages

1653-1660

Publication/Series

Organic and Biomolecular Chemistry

Volume

9

Issue

5

Document type

Journal article

Publisher

Royal Society of Chemistry

Topic

  • Organic Chemistry

Status

Published

ISBN/ISSN/Other

  • ISSN: 1477-0539