期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 24, 页码 13380-13387出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202101496
关键词
glycopeptides; glycoproteins; native chemical ligation; oligosaccharides; serum clearance
资金
- Deutsche Forschungsgemeinschaft [DFG UN63/5-1 + SPP 1623]
A library of glycoforms of human interleukin 6 (IL-6) was generated using semisynthesis, and their in vivo plasma clearance rates in rats were evaluated. The results showed that IL-6 glycoforms with different structures exhibited varying clearance rates in the body, with 2,6-sialylated glycoforms of IL-6 being cleared faster in most cases.
A library of glycoforms of human interleukin 6 (IL-6) comprising complex and mannosidic N-glycans was generated by semisynthesis. The three segments were connected by sequential native chemical ligation followed by two-step refolding. The central glycopeptide segments were assembled by pseudoproline-assisted Lansbury aspartylation and subsequent enzymatic elongation of complex N-glycans. Nine IL-6 glycoforms were synthesized, seven of which were evaluated for in vivo plasma clearance in rats and compared to non-glycosylated recombinant IL-6 from E. coli. Each IL-6 glycoform was tested in three animals and reproducibly showed individual serum clearances depending on the structure of the N-glycan. The clearance rates were atypical, since the 2,6-sialylated glycoforms of IL-6 cleared faster than the corresponding asialo IL-6 with terminal galactoses. Compared to non-glycosylated IL-6 the plasma clearance of IL-6 glycoforms was delayed in the presence of larger and multibranched N-glycans in most cases
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