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.

Arbutin, a natural glycoside, is well known as a commercial tyrosinase inhibitor, and thus, to prevent pigmentary disorders of skin. In fact, tyrosinase is involved in the biosynthesis of melanin, the skin main pigment. However, arbutin is subject to hydrolysis, which limits its bioactivity. In general, thioglycosides are known to be very resistant to both chemical and enzymatic hydrolysis, which increases the interaction time with their biological targets. A biocatalytic approach allowed us to access to thioglycosidic analogs of arbutin in a green approach with good to excellent yields. Such compounds have then been tested as tyrosinase inhibitors as well as inhibitors of melanin transfer from melanocytes to keratinocytes. This latter mechanism takes place via lectin (or lectin‐like) receptors present on the cells surface. p‐Aminophenyl β‐D‐thiogalactopyranoside appears to be an excellent candidate thanks to its tyrosinase inhibitory activity comparable to arbutin, while having the ability to interact with glycan receptors allowing to reduce melanin transfer.

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