Natural Glycoforms of Human Interleukin 6 show atypical plasma clearance

Titelangaben

Unverzagt, Carlo ; Reif, Andreas ; Lam, Kevin ; Weidler, Sascha ; Lott, Marie ; Boos, Irene ; Lokau, Juliane ; Bretscher, Christian ; Mönnich, Manuel ; Perkams, Lukas ; Schmälzlein, Marina ; Graf, Christopher G. F. ; Fischer, Jan-Patrick ; Lechner, Carolin ; Hallstein, Kerstin ; Becker, Stefan ; Weyand, Michael ; Steegborn, Clemens ; Schultheiss, Gerhard ; Rose-John, Stefan ; Garbers, Christoph:
Natural Glycoforms of Human Interleukin 6 show atypical plasma clearance.
In: Angewandte Chemie International Edition. Bd. 60 (2021) Heft 24 . - S. 13380-13387.
ISSN 1521-3773
DOI: https://doi.org/10.1002/anie.202101496

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Abstract

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, 7 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.