Probing the acceptor substrate binding site of Trypanosoma cruzi trans-sialidase with systematically modified substrates and glycoside libraries.
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.
Centre for Biomolecular Sciences, University of St Andrews, St Andrews, UK KY16 9ST.
Jennifer A
JA
Harrison
K P Ravindranathan
KP
Kartha
Eric J L
EJ
Fournier
Todd L
TL
Lowary
Carles
C
Malet
Ulf J
UJ
Nilsson
Ole
O
Hindsgaul
Sergio
S
Schenkman
James H
JH
Naismith
Robert A
RA
Field
D001665:Binding Sites; D006023:Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D006027:Glycosides / Q000737:chemistry* / Q000378:metabolism; D015394:Molecular Structure; D009439:Neuraminidase / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity; D014349:Trypanosoma cruzi / Q000201:enzymology*
D006023:Glycoproteins; D006027:Glycosides; D054852:Small Molecule Libraries; C069715:trans-sialidase; D009439:Neuraminidase
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