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Towards the development and discovery of inhibitors for Trypanosoma cruzi trans-sialidase Robinson, Kyle Brian

Abstract

The parasite Trypanosoma cruzi displays a trans-sialidase (TcTS) on its surface that is hypothesized to be a therapeutic target for Chagas disease. TcTS transfers sialic acid from the cells of infected hosts to the surface of the pathogenic parasite, masking it from immune recognition and enhancing cellular invasion. The design of TcTS inhibitors has been largely unsuccessful to date. Accordingly, this work aims to identify new TcTS inhibitors, both by modifying existing inhibitors and by screening natural product and peptide libraries to discover new chemical scaffolds for this purpose. First, analogues of the established mechanism-based inhibitor, difluorosialic acid (DFSA), were investigated in search of increased potency and selectivity for TcTS. The synthesis and kinetic analysis of nine C9 amide-linked DFSAs and seven N-acyl modified DFSAs was explored to this end. One candidate was identified that inhibited TcTS 10-fold better than the unmodified precursor. Further, TcTS showed a tolerance for the C5 functionalized inhibitors, a fact that can be leveraged – together with C9 substitution – for specificity versus human neuraminidases. Next, a library of ~1000 marine organism extracts was screened for TcTS inhibition, from which five hits were selected. Bioassay-guided isolation and structural determination of the active chemicals afforded two new natural product inhibitors of TcTS with IC50 values

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Attribution-NonCommercial-NoDerivatives 4.0 International