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Erythropoietin Derived by Chemical Synthesis

Science  13 Dec 2013:
Vol. 342, Issue 6164, pp. 1357-1360
DOI: 10.1126/science.1245095

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EPO via Total Synthesis

Erythropoietin (EPO) is a hormone involved in the production of red blood cells. Synthetic EPO produced via genetically engineered cell cultures is used to treat anemia and—more controversially—to boost athletic performance. EPO is a glycoprotein, and though its protein component is well-defined, both natural and synthetic EPO exhibit a wide range of attached oligosaccharides. Wang et al. (p. 1357; see the Perspective by Hsieh-Wilson and Griffin) prepared an EPO sample by a chemical synthesis that maintains a uniform pattern of attached sugars throughout, which may prove helpful in the analysis of how variation in the sugar components of EPO impact function.

Abstract

Erythropoietin is a signaling glycoprotein that controls the fundamental process of erythropoiesis, orchestrating the production and maintenance of red blood cells. As administrated clinically, erythropoietin has a polypeptide backbone with complex dishomogeneity in its carbohydrate domains. Here we describe the total synthesis of homogeneous erythropoietin with consensus carbohydrate domains incorporated at all of the native glycosylation sites. The oligosaccharide sectors were built by total synthesis and attached stereospecifically to peptidyl fragments of the wild-type primary sequence, themselves obtained by solid-phase peptide synthesis. The glycopeptidyl constructs were joined by chemical ligation, followed by metal-free dethiylation, and subsequently folded. This homogeneous erythropoietin glycosylated at the three wild-type aspartates with N-linked high-mannose sialic acid–containing oligosaccharides and O-linked glycophorin exhibits Procrit-level in vivo activity in mice.

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