A novel synthetic derivative of human erythropoietin designed to bind to glycosaminoglycans.
To synthesize long-acting and antiangiogenic erythropoietin to be clinically applied for treatment of patients with solid tumors, we synthesized a hybrid molecule of human erythropoietin added onto the C-terminus with a heparin-binding motif of human PLGF-2 to develop a novel derivative of long-acting and antiangiogenic erythropoietin: heparin-binding erythropoietin (HEPO), and studied the characteristics of this novel erythropoietin derivative. HEPO cDNA was synthesized, expressed in insect cells, and the protein was purified using a heparin-sepharose affinity column. The erythropoietic and angiogenic effects of the partially purified protein were analyzed in vitro and in vivo. The erythropoietic activity of the protein was equivalent to natural EPO in vitro. In vivo administration of the protein to mice revealed its long-acting erythropoietic activity as expected. Administration of the protein inhibited angiogenesis in a mouse limb ischemia model. In conclusion, the heparin-binding motif of PLGF-2 may act as, so to speak, a superendostatin. This novel long-acting erythropoietin derivative may have an advantage to inhibit tumor growth while preserving hematopoietic and tissue-protective effects.
First Department of Internal Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan.
Masato
M
Moriyama
Ken
K
Toba
Haruo
H
Hanawa
Kiminori
K
Kato
Takao
T
Yanagawa
Tsugumi
T
Takayama
Takuya
T
Ozawa
Hironori
H
Kobayashi
Masato
M
Higuchi
Hideki
H
Saito
Yoshifusa
Y
Aizawa
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015195:Drug Design; D004921:Erythropoietin / Q000138:chemical synthesis / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000502:physiology; D011994:Recombinant Proteins / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism
D006025:Glycosaminoglycans; D011994:Recombinant Proteins; D004921:Erythropoietin