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

• Published in: Chemistry : a European journal Vol. 21; no. 30; pp. 10903 - 10912
• Main Authors: Birikaki, Lémonia, Pradeau, Stéphanie, Armand, Sylvie, Priem, Bernard, Márquez-Domínguez, Luis, Reyes-Leyva, Julio, Santos-López, Gerardo, Samain, Eric, Driguez, Hugues, Fort, Sébastien
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 20-07-2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc; Wiley-VCH Verlag
• Subjects: Acids; Agglutinins - metabolism; Animals; Bacteria; Cattle; Chemical Sciences; Chemistry; chemoenzymatic synthesis; Cholera; Escherichia coli; Escherichia coli - genetics; Escherichia coli - metabolism; glycomimetics; Hemagglutinins - metabolism; Hydrolysis; Influenza; Influenza virus; Inhibition; Life Sciences; Maackia - metabolism; Metabolic Engineering; neuraminic acids; Neuraminic Acids - chemical synthesis; Neuraminic Acids - chemistry; Neuraminic Acids - metabolism; Neuraminic Acids - pharmacology; Neuraminidase - antagonists & inhibitors; Oligosaccharides; Oligosaccharides - chemical synthesis; Oligosaccharides - chemistry; Oligosaccharides - metabolism; Oligosaccharides - pharmacology; Sialic Acids - chemical synthesis; Sialic Acids - chemistry; Sialic Acids - metabolism; Sialic Acids - pharmacology; Strategy; Synthesis; Vibrio; Vibrio cholerae; Vibrio cholerae - enzymology; Viruses; influenza; glycomimetics; neuraminic acids; chemoenzymatic synthesis; oligosaccharides
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201500708

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 Analogues of GM3 and GM2 ganglioside saccharidic portions where the acetyl group of NeuNAc has been replaced by a phenylacetyl (PhAc) or a propanoyl (Prop) moiety have been efficiently prepared with metabolically engineered E. coli bacteria.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.
Flu fight: Sialylated oligosaccharides containing C5‐modified neuraminic acids were efficiently synthesized by a chemo‐enzymatic approach involving metabolically engineered E. coli cells. GM3NPhAc and GM3NProp inhibit both Maackia amurensis hemagglutinin and Vibrio cholerae neuraminidase without being hydrolyzed. Inhibition of influenza virus sialidase by GM3NPhAc also offers new perspectives in the fight against flu infection (see picture).