Convergent chemical synthesis of [lysine(24,38,83)] human erythropoietin.

Abstract

Erythropoietin (EPO) is a glycoprotein hormone that plays important roles in regulating the production of red blood cells (erythrocytes).[1] Since human EPO was first isolated and purified from urine in 1977,[2] the structure and physiological properties of EPO have been thoroughly studied.[3] Mature human EPO found in nature consists of a polypeptide chain of 165 amino acids with four covalently attached oligosaccharides,[4] one of which is an O-linked oligosaccharide at Ser126, and the other three are N-linked oligosaccharides at residues Asn24, 38, 83.[ 5 ] EPO is used as a therapeutic agent to treat anemia caused by chronic kidney disease.[6] Commercial EPO is prepared using recombinant DNA technology. The carbohydrate moieties of both native and recombinant EPO[7] are heterogenerous and composed of multiple glycans with different lengths and composition at each glycosylation site.[5a,8] This heterogeneity makes it difficult to evaluate the effects of carbohydrate on EPO’s pharmacokinetic properties and, more importantly, complicates the understanding of mechanism of EPO’s action at the molecular level. For these reasons, it is important to develop an alternative strategy to prepare homogeneous EPO.