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Natural Glycoforms of Human Interleukin 6 Show Atypical Plasma Clearance
Author(s) -
Reif Andreas,
Lam Kevin,
Weidler Sascha,
Lott Marie,
Boos Irene,
Lokau Juliane,
Bretscher Christian,
Mönnich Manuel,
Perkams Lukas,
Schmälzlein Marina,
Graf Christopher,
Fischer JanPatrick,
Lechner Carolin,
Hallstein Kerstin,
Becker Stefan,
Weyand Michael,
Steegborn Clemens,
Schultheiss Gerhard,
RoseJohn Stefan,
Garbers Christoph,
Unverzagt Carlo
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202101496
Subject(s) - glycan , chemistry , clearance , recombinant dna , glycopeptide , in vivo , glycosylation , biochemistry , human plasma , glycoprotein , chromatography , biology , medicine , microbiology and biotechnology , urology , gene , antibiotics
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