Natural Glycoforms of Human Interleukin 6 Show Atypical Plasma Clearance

Overview

Journal Angew Chem Int Ed Engl

Specialty Chemistry

Date 2021 Mar 23

PMID 33756033

Citations 9

Authors

Andreas Reif

Kevin Lam

Sascha Weidler

Marie Lott

Irene Boos

Juliane Lokau

Christian Bretscher

Manuel Monnich

Lukas Perkams

Marina Schmalzlein

Christopher Graf

Jan-Patrick Fischer

Carolin Lechner

Kerstin Hallstein

Stefan Becker

Michael Weyand

Clemens Steegborn

Gerhard Schultheiss

Stefan Rose-John

Christoph Garbers

Carlo Unverzagt

Affiliations

Soon will be listed here.

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, 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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