Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

Submitting author affiliation:
The University of Manchester - Manchester Institute of Biotechnology (MIB), Manchester, United Kingdom

Beilstein Arch. 2021, 202177.

Published 08 Nov 2021



Sialic acid is the natural substrate for sialidases and its chemical modification has been a useful approach to generate potent and selective inhibitors. Aiming at advancing the discovery of selective Trypanosoma cruzi trans-sialidase (TcTS) inhibitors, we have synthesised a small series of anomeric 1,2,3-triazole-linked sialic acid derivatives in good yields and high purity via copper-catalysed azide-alkyne cycloaddition (CuAAC, click chemistry) and evaluated their activity towards TcTS and neuraminidase. Surprisingly, the compounds showed practically no TcTS inhibition, whereas ca. 70% inhibition was observed for neuraminidase in relation to the analogues bearing hydrophobic substituents and ca. 5% for more polar substituents. These results suggest that polarity changes are less tolerated by neuraminidase due to the big difference in impact of hydrophobicity upon inhibition, thus indicating a simple approach to differentiate both enzymes. Moreover, such selectivity might be reasoned based on a possible steric hindrance caused by a bulky hydrophobic loop that sits over TcTS active and may prevent the hydrophobic inhibitors from binding. The present study is a step forward in exploiting subtle structural differences in sialidases that need to be addressed in order to achieve a selective inhibition.

Keywords: Trans-sialidase, neuraminidase, sialic acid, 1,2,3-triazole, inhibition

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de Andrade, P.; Ahmadipour, S.; Field, R. A. Beilstein Arch. 2021, 202177. doi:10.3762/bxiv.2021.77.v1

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