Chemoenzymatic Syntheses of Sialylated Oligosaccharides Containing C5‐Modified Neuraminic Acids for Dual Inhibition of Hemagglutinins and Neuraminidases

A fast chemoenzymatic synthesis of sialylated oligosaccharides containing C5‐modified neuraminic acids is reported. Analogues of GM₃ and GM₂ ganglioside saccharidic portions where the acetyl group of NeuNAc has been replaced by a phenylacetyl (PhAc) or a propanoyl (Prop) moiety have been efficiently prepared with metabolically engineered E. coli bacteria. GM₃ analogues were either obtained by chemoselective modification of biosynthetic N‐acetyl‐sialyllactoside (GM₃NAc) or by direct bacterial synthesis using C5‐modified neuraminic acid precursors. The latter strategy proved to be very versatile as it led to an efficient synthesis of GM₂ analogues. These glycomimetics were assessed against hemagglutinins and sialidases. In particular, the GM₃NPhAc displayed a binding affinity for Maackia amurensis agglutinin (MAA) similar to that of GM₃NAc, while being resistant to hydrolysis by Vibrio cholerae (VC) neuraminidase. A preliminary study with influenza viruses also confirmed a selective inhibition of N1 neuraminidase by GM₃NPhAc, suggesting potential developments for the detection of flu viruses and for fighting them.