Multivalent Thiosialosides and Their Synergistic Interaction with Pathogenic Sialidases

Abstract : Sialidases (SAs) hydrolyze sialyl residues from glycoconjugates of the eukaryotic cell surface and are virulence factors expressed by pathogenic bacteria, viruses, and parasites. The catalytic domains of SAs are often flanked with carbohydrate-binding module(s) previously shown to bind sialosides and to enhance enzymatic catalytic efficiency. Herein, non-hydrolyzable multivalent thiosialosides were designed as probes and inhibitors of V. cholerae, T. cruzi, and S. pneumoniae (NanA) sialidases. NanA was truncated from the catalytic and lectinic domains (NanA-L and NanA-C) to probe their respective roles upon interacting with sialylated surfaces and the synthetically designed di- and polymeric thiosialosides. The NanA-L domain was shown to fully drive NanA binding, improving affinity for the thiosialylated surface and compounds by more than two orders of magnitude. Importantly, each thiosialoside grafted onto the polymer was also shown to reduce NanA and NanA-C catalytic activity with efficiency that was 3000-fold higher than that of the monovalent thiosialoside reference. These results extend the concept of multivalency for designing potent bacterial and parasitic sialidase inhibitors.
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Submitted on : Monday, May 27, 2019 - 3:56:34 PM
Last modification on : Thursday, November 21, 2019 - 5:44:06 PM

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Yoan Brissonnet, Coralie Assailly, Amelie Saumonneau, Julie Bouckaert, Mike Maillasson, et al.. Multivalent Thiosialosides and Their Synergistic Interaction with Pathogenic Sialidases. Chemistry - A European Journal, Wiley-VCH Verlag, 2019, 25 (9), pp.2358-2365. ⟨10.1002/chem.201805790⟩. ⟨hal-02140863⟩

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