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Towards specific inactivators of Trypanosoma cruzi trans-sialidase

University of British Columbia

The Trypanosoma cruzi (T. cruzi) trans-sialidase is thought to be an essential enzyme for infection by T. cruzi since sialic acid is needed for its nutrition and pathogenesis yet T. cruzi cannot biosynthesize sialic acid. The overall goal of this project is to identify a tight binding and specific inactivator of the T. cruzi trans-sialidase (TcTS). A library of mechanism-based inactivators of TcTS was synthesized based upon the known inactivator 9-azido-3-fluorosialyl fluoride (parent inactivator) by click chemistry with a series of alkynes in yields of 40-81%. Kinetic parameters for the clicked inactivators and its parent were determined using 5-acetamido-3,5-dideoxy-2-(4-trifluoromethylumbelliferyl)-D-glycero-α-D-galacto-non-2-ulopyranosonic acid as substrate. Inactivation parameters for the clicked inactivators were generally inferior to those of parent compound 9-azido-3-fluorosialyl fluoride. The substrate binding pocket of TcTS prefers non-polar moieties near the 9-position, especially aliphatic rings. It was also found that TcTS can tolerate negative charges better than positive charges at this position. These results suggest that improved reagents might incorporate moieties attached to C-9 through an amide or an ether linker rather than through a triazole.

Text

2013-03-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/44074

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/