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Synthesis of Sialidase-Resistant Oligosaccharide and Antibody Glycoform Containing α2,6-Linked 3Fᵃˣ-Neu5Ac

Lo, Hong-Jay, Krasnova, Larissa, Dey, Supriya, Cheng, Ting, Liu, Haitian, Tsai, Tsung-I, Wu, Kevin Binchia, Wu, Chung-Yi, Wong, Chi-Huey
Journal of the American Chemical Society 2019 v.141 no.16 pp. 6484-6488
antibodies, bioactive properties, catalytic activity, cleavage (chemistry), glycoproteins, glycosides, glycosidic linkages, oligosaccharides, pharmacokinetics, polysaccharides, sialidase, synthesis, therapeutics
Fluorinated glycosides are known to resist the glycosidase-catalyzed glycosidic bond cleavage; however, the synthesis of such glycans, especially 3-fluoro-sialic acid (3F-Neu5Ac) containing sialosides, has been a major challenge. Though the enzymatic synthesis of α-2,3-linked 3F-sialosides was reported, until recently there has not been any effective method available for the synthesis of 3F-sialosides in the α-2,6-linkage. In order to understand the biological effect of such modification, we report here a chemical synthesis of 3Fᵃˣ-Neu5Ac-α2,6-Gal as a building block for the assembly of 3Fᵃˣ-Neu5Ac-containing sialosides and a representative homogeneous antibody glycoform. Our results showed that the sialosides are stable under sialidase catalysis and the rituximab glycoform with a sialylated complex-type biantennary glycan terminated with 3Fᵃˣ-Neu5Ac in the α-2,6-linkage (α2,6-F-SCT) has a similar binding avidity as its parent glycoform. These findings open up new opportunities for the development of therapeutic glycoproteins with improved pharmacokinetic parameters.