Genomics Research Center , Academia Sinica , 128 Academia Road , Section 2, Nanakang, Taipei 115 , Taiwan.
The Scripps Research Institute , 10550 North Torrey Pines Road , La Jolla , California 92037 , United States.
J Am Chem Soc. 2019 Apr 24;141(16):6484-6488. doi: 10.1021/jacs.9b01991. Epub 2019 Apr 15.
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 3F-Neu5Ac-α2,6-Gal as a building block for the assembly of 3F-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 3F-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.
氟代糖苷已知能够抵抗糖苷酶催化的糖苷键断裂；然而，此类糖的合成，特别是含有唾液酸的 3-氟唾液酸（3F-Neu5Ac）的唾液酸苷，一直是一个重大挑战。尽管已经报道了α-2,3 连接的 3F-唾液酸苷的酶促合成，但直到最近，还没有有效的方法可用于合成α-2,6 连接的 3F-唾液酸苷。为了了解这种修饰的生物学效应，我们在此报道了 3F-Neu5Ac-α2,6-Gal 的化学合成，作为组装含有 3F-Neu5Ac 的唾液酸苷和代表性均相抗体糖型的构建块。我们的结果表明，唾液酸苷在唾液酸酶催化下稳定，并且具有 3F-Neu5Ac 在α-2,6-连接（α2,6-F-SCT）上末端的唾液酸化复杂型双天线聚糖的利妥昔单抗糖型与其亲本糖型具有相似的结合亲和力。这些发现为开发具有改善药代动力学参数的治疗性糖蛋白开辟了新的机会。
