Abstract
Bioorthogonal chemical reporters, in synergy with click chemistry, have emerged as a key technology for tagging complex glycans in living cells. This strategy relies on the fact that bioorthogonal chemical reporters are highly reactive species while being biologically noninvasive. Here, we report that chemical reporters and especially sydnones may have, on the contrary, enormous impact on biomolecule processing enzymes. More specifically, we show that editing cell-surface sialic acid-containing glycans (sialosides) with bioorthogonal chemical reporters can significantly affect the activity of bacterial sialidases, enzymes expressed by bacteria during pathogenesis for cleaving sialic acid sugars from mammalian cell-surface glycans. Upon screening various chemical reporters, as well as their position on the sialic acid residue, we identified that pathogenic bacterial sialidases were unable to cleave sialosides displaying a sydnone at the 5-position of sialic acids in vitro as well as in living cells. This study highlights the importance of investigating more systematically the metabolic fate of glycoconjugates modified with bioorthogonal reporters.