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J Am Chem Soc. 2019 Apr 24;141(16):6484-6488. doi: 10.1021/jacs.9b01991. Epub 2019 Apr 15.

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

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1
Genomics Research Center , Academia Sinica , 128 Academia Road , Section 2, Nanakang, Taipei 115 , Taiwan.
2
The Scripps Research Institute , 10550 North Torrey Pines Road , La Jolla , California 92037 , United States.

Abstract

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.

PMID:
30969765
DOI:
10.1021/jacs.9b01991

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