Studies on human erythropoietin (EPO) demonstrated that there is a direct relationship between the sialic acid-containing carbohydrate content of the molecule and its serum half-life and in vivo biological activity, but an inverse relationship with its receptor-binding affinity. These observations led to the hypothesis that increasing the carbohydrate content, beyond that found naturally, would lead to a molecule with enhanced biological activity. Hyperglycosylated recombinant human EPO (rHuEPO) analogues were developed to test this hypothesis. Darbepoetin alfa (novel erythropoiesis stimulating protein, NESP, ARANESPTM, Amgen Inc, Thousand Oaks, CA), which was engineered to contain 5 N-linked carbohydrate chains (two more than rHuEPO), has been evaluated in preclinical animal studies. Due to its increased sialic acid-containing carbohydrate content, NESP is biochemically distinct from rHuEPO, having an increased molecular weight and greater negative charge. Compared with rHuEPO, it has an approximate 3-fold longer serum half-life, greater in vivo potency, and can be administered less frequently to obtain the same biological response. NESP is currently being evaluated in human clinical trials for treatment of anaemia and reduction in its incidence.© 2001 Cance Cance Cancer Research Campaign

/pdf/development-and-characterization-of-novel-erythropoiesis-44io75c75i.pdf

Development and characterization of novel erythropoiesis stimulating protein (NESP)

https://www.exphem.org/article/S0301-472X(03)00006-7/pdf

Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin

Structural characterization of human erythropoietin.

Comparative study of the asparagine-linked sugar chains of human erythropoietins purified from urine and the culture medium of recombinant Chinese hamster ovary cells

Studies on human erythropoietin (EPO) demonstrated that there is a direct relationship between the sialic acid-containing carbohydrate content of the molecule and its serum half-life and in vivo biological activity, but an inverse relationship with its receptor binding affinity These observations led to the hypothesis that increasing the carbohydrate content, beyond that found naturally, would lead to a molecule with enhanced biological activity Hyperglycosylated recombinant human EPO (rHuEPO) analogues were developed to test this hypothesis Darbepoetin alfa (novel erythropoiesis stimulating protein, NESP), which was engineered to contain five N-linked carbohydrate chains (two more than rHuEPO), has been evaluated in preclinical animal studies Due to its increased sialic acid-containing carbohydrate content, NESP is biochemically distinct from rHuEPO, having an increased molecular weight and greater negative charge Compared with rHuEPO, it has an approximately 3-fold longer serum half-life, greater in vivo potency, and can be administered less frequently to obtain the same biological response NESP is currently being evaluated in human clinical trials for treatment of anaemia and reduction in its incidence

/pdf/development-and-characterization-of-novel-erythropoiesis-3uptavntvr.pdf

https://link.springer.com/content/pdf/10.1134/S0026893322030153.pdf

Multimodal Magnetic Resonance and Fluorescence Imaging of the Induced Pluripotent Stem Cell Transplantation in the Brain

Erythropoietin (epo) is the glycoprotein hormone that induces normal red cell differentiation. Reaction of native or denatured epo with either [3H]iodoacetic acid or N-ethyl-2-[3H]maleimide did not result in the incorporation of any significant amount of radioactivity. Radiolabeling took place only if the protein were denatured before reduction and alkylation. When reduction was carried out in the presence of 6 M guanidine HCl, about 3.7 mol N-ethyl-2[3H]maleimide were covalently linked per mol epo. These results show that there are no free, accessible sulfhydryl groups in epo; there are two internal disulfide bonds. When epo was reduced in the presence of 6 M guanidine HCl and then reoxidized and the guanidine removed, about 85% of the biological activity was regenerated. The biological activity was lost irreversibly if the sulfhydryl groups were alkylated. Limited proteolysis of [3H]epo (labeled at sialic acid residues of the oligosaccharide chains) showed that it consists of two rather trypsin-resistant domains, each having a mol wt of about 16,000, connected by a small region of protein that is trypsin sensitive. The two large fragments contain most of the label. Biological activity and immunoreactivity are lost after limited tryptic proteolysis. Complexing epo with a neutralizing antibody protects its activity from proteolysis.

Some chemical properties of human erythropoietin

The carbohydrate composition of human erythropoietin (epo) was determined by micro-GLC. Enzymic removal of most of the sugars results in aggregation of glycosidase-treated epo, loss of biological activity when assayed in mice, and retention of activity when assayed in marrow cell cultures or by RIA. Endoglycosidase F causes the removal of most of the carbohydrates indicating that the oligosaccharides are asparagine linked. The lack of O-linked sugar is confirmed by the absence of N-acetylgalactosamine. These findings indicate that the oligosaccharide portion of epo, although required for action in vivo, is not required for interaction with the target cells of the blood-forming system.

The Role of Carbohydrate in Erythropoietin Action

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Multimodal Magnetic Resonance and Fluorescence Imaging of the Induced Pluripotent Stem Cell Transplantation in the Brain

Some chemical properties of human erythropoietin

The Role of Carbohydrate in Erythropoietin Action