Seitz, Carina

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Seitz
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Carina
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Synthesis of Erythropoietins Site‐Specifically Conjugated with Complex‐Type N‐Glycans

2019-08-01, Streichert, Katharina, Seitz, Carina, Hoffmann, Eugenia, Boos, Irene, Jelkmann, Wolfgang, Brunner, Thomas, Unverzagt, Carlo, Rubini, Marina

The biological activity of glycoprotein hormone erythropoietin (EPO) is dependent mainly on the structure of its N-linked glycans. We aimed at readily attaching N-glycans to EPO via defined alkyne groups. EPO variants with an alkyne bearing amino acid (Plk) at the N-glycosylation sites 24, 38 and 83 were obtained by amber suppression followed by refolding. Click-conjugation of the alkinyl EPOs with biantennary N-glycan azides provided biologically active site-specifically modified EPO glycoconjugates.

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Stabilization of bacterially expressed erythropoietin by single site-specific introduction of short branched PEG chains at naturally occurring glycosylation sites

2016-05-24, Hoffmann, Eugenia, Streichert, Katharina, Nischan, Nicole, Seitz, Carina, Brunner, Thomas, Schwagerus, Sergej, Hackenberger, Christian P. R., Rubini, Marina

The covalent attachment of polyethylene glycol (PEG) to therapeutic proteins can improve their physicochemical properties. In this work we utilized the non-natural amino acid p-azidophenylalanine (pAzF) in combination with the chemoselective Staudinger-phosphite reaction to install branched PEG chains to recombinant unglycosylated erythropoietin (EPO) at each single naturally occurring glycosylation site. PEGylation with two short 750 or 2000 Da PEG units at positions 24, 38, or 83 significantly decreased unspecific aggregation and proteolytic degradation while biological activity in vitro was preserved or even increased in comparison to full-glycosylated EPO. This site-specific bioconjugation approach permits to analyse the impact of PEGylation at single positions. These results represent an important step towards the engineering of site-specifically modified EPO variants from bacterial expression with increased therapeutic efficacy.