Unverzagt

Due to its medical importance erythropoietin (EPO) is one of the best-studied recombinant therapeutic glycoproteins. In seminal studies it was revealed that the function of erythropoietin is highly dependent on the presence and the structure of its carbohydrate moieties. Despite many efforts the isolation of
homogeneous EPO glycoforms is still not feasible and biological studies can only use mixtures of glycoforms. Thus synthetic alternatives are desirable aiming at the generation of pure EPO glycoforms needed for more detailed structure-activity-relationships.

To this end we propose the semisynthesis of EPO via expressed protein ligation and chemically synthesized glycopeptide thioesters with all natural linkages. This goal requires new synthetic methodology allowing the installation of multiple Nglycosylation sites. Studies will be conducted in order to correlate the sugar composition to the activity of the protein, to intrinsic stability and folding as well as to biodistribution. The synthetic array of natural glycoforms of EPO should provide insights into the various roles of carbohydrates in glycoproteins and may guide the future engineering of glycoforms.

A. Reif, S. Siebenhaar, A. Tröster, M. Schmälzlein, C. Lechner, P. Velisetty, K. Gottwald, C. Pöhner, I. Boos, V. Schubert, S. Rose-John, C. Unverzagt
Angew. Chem. 2014, 126, 12321-12327
Angew. Chem. Int. Ed. 2014, 53, 12125-12131
Semisynthesis of Biologically Active Glycoforms of the Human Cytokine Interleukin 6
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C. Pöhner, v. Ullmann, R. Hilpert, E. Samain, C. Unverzagt
Tetrahedron Lett. 2014, 55, 2197-2200
Chemoselective coupling of sugar oximes and α-ketoacids to glycosyl amides and N-glycopeptides
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C. Unverzagt, Y. Kajihara
Chem. Soc. Rev. 2013, 42, 4408-4420
Chemical assembly of N-glycoproteins: a refined toolbox to address a ubiquitous posttranslational modification
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V. Ullmann, M. Rädisch, I. Boos, J. Freund, C. Pöhner, S. Schwarzinger, C. Unverzagt
Angew. Chem. Int. Ed. 2012, 51, 11566-11570
Convergent Solid Phase Synthesis of N-Glycopeptides supported by Pseudoprolines at Consensus Ser/Thr Residues
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D. Ott, J. Seifert, I. Prahl, M. Niemietz, J. Hoffman, J. Guder, M. Mönnich, C. Unverzagt
Eur. J. Org. Chem. 2012, 26, 5054-5068
Modular Synthesis of Core Fucosylated N-Glycans
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