Studies for the improvement of erythropoietin in vivo activity = 에리스로포이에틴의 활성 개선에 관한 연구

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Erythropoietin, Epo, is a hematopoietic factor promoting production and differentiation of erythroid precursor cells and the recombinant human Epo has been used for the treatment of anemia. Four fusion proteins were designed and constructed by adding peptides on the carboxy terminus of Epo with no linker in order to increase the half-life of Epo. Epo-CTP is a fusion protein of Epo and carboxy terminal peptide (CTP, 28 a.a) of human chorionic gonadotropin beta subunit. Epo-ATP is a deglycosylated mutant of the Epo-CTP by changing Ser to Ala on CTP. Epo-LTP is a fusion protein of Epo and C-terminal half region (178 a.a) of human thrombopoietin (hTpo). And Epo-STP consists of Epo and a short C-terminal peptide (17 a.a) of hTpo. CHO cells were transformed by the expression vectors, pcDNA3.1, of Epo derivatives. Secretion of the Epo derivatives from the cell was not influenced by the peptide addition on the Epo terminus. Also, in vitro bioassay showed that receptor binding of the Epo derivatives were not interfered with the added peptides. The expressed Epo derivatives were purified using immunoaffinity chromatography. Rats were administered with the Epo derivatives intravenously and subcutaneously, which it was shown that CTP and ATP similarly doubled terminal half-life of Epo in spite of their small size. So, it is apparent that the in vivo stabilizing effect of CTP on Epo was resulted from the peptide itself rather than its O-glycosylation. Epo-STP showed longer half-life than Epo but relatively shorter than other derivatives. This might be due to the lost of one N-glycosylation and the different glycosylation type. The sustained elimination of Epo-LTP can be resulted from the protection of LTP having bulky glycosylation in both i.v and s.c pharmacokinetic study. Epo-LTP was slowly absorbed than other derivatives and it can be result from the large size. In vivo activity of Epo derivatives in subcutaneously administered mice was confirmed and is consistent with t...
Yoo, Ook-Joonresearcher유욱준researcher
한국과학기술원 : 생물과학과,
Issue Date
180985/325007 / 000965271

학위논문(박사) - 한국과학기술원 : 생물과학과, 2003.2, [ ix, 100 p. ]


in vivo activity; erythropoietin; erythropoietin derivative; 변형 에리스로포이에틴; 생체내 활성; 에리스로포이에틴

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