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N-Terminal Modification with Pseudo-Bifunctional PEG-Hexadecane Markedly Improves the Pharmacological Profile of Human Growth Hormone
Wu, Ling1,2; Ji, Shaoyang1; Hu, Tao1
2015-05-01
Source PublicationMOLECULAR PHARMACEUTICS
ISSN1543-8384
Volume12Issue:5Pages:1402-1411
Abstract

Human growth hormone (hGH) has been used to treat children with short stature, renal failure, and Turner's syndrome. However, clinical application of hGH suffers from its short plasma half-life and low bioavailability. PEGylation and albumin binding are two of the most effective approaches to prolong the plasma half-life of hGH. However, the steric shielding effects of polyethylene glycol (PEG) and albumin can drastically decrease the bioactivity of hGH, which is opposite to the increased pharmacokinetics (PK). In the present study, a long-acting hGH with markedly improved pharmacological profile was rationally designed and prepared by N-terminal modification of hGH with pseudo-bifunctional PEG-hexadecane by using PEG (3.5 kDa or 10 kDa) as the linker. PEGylation and albumin binding with hexadecane can increase the hydrodynamic volume and decrease the immunogenicity of hGH, which thereby markedly increases the PK of hGH. Since N-terminus is far from the bioactive domain of hGH, N-terminal modification of hGH can minimize the steric shielding effects on the bioactive domain of hGH. Hexadecane-bound albumin can be slowly released from hGH during the in vivo circulation, which can slowly restore the bioactivity of hGH. Thus, the high bioactivity of PEG-hexadecane modified hGH (hGH-PEG-HD) was synergistically achieved by N-terminal modification with pseudo-bifunctional PEG-hexadecane and slow-release of albumin. The high pharmacodynamics (PD) of hGH-PEG-HD was due to the synergistic effect of the high bioactivity and the overall increased PK.

KeywordGrowth Hormone Pegylation Hexadecane Albumin Binding
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
DOI10.1021/mp500680p
Indexed BySCI
Language英语
WOS KeywordDRUG-DELIVERY ; POLY(ETHYLENE GLYCOL) ; ALBUMIN ; STAPHYLOKINASE ; PEGYLATION ; LINKER ; PHARMACOKINETICS ; PHARMACODYNAMICS ; CONJUGATION ; BIOACTIVITY
WOS Research AreaResearch & Experimental Medicine ; Pharmacology & Pharmacy
WOS SubjectMedicine, Research & Experimental ; Pharmacology & Pharmacy
WOS IDWOS:000354075700007
Citation statistics
Document Type期刊论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/16776
Collection生化工程国家重点实验室
Affiliation1.Chinese Acad Sci, Inst Proc Engn, Natl Key Lab Biochem Engn, Beijing 100190, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100190, Peoples R China
Recommended Citation
GB/T 7714
Wu, Ling,Ji, Shaoyang,Hu, Tao. N-Terminal Modification with Pseudo-Bifunctional PEG-Hexadecane Markedly Improves the Pharmacological Profile of Human Growth Hormone[J]. MOLECULAR PHARMACEUTICS,2015,12(5):1402-1411.
APA Wu, Ling,Ji, Shaoyang,&Hu, Tao.(2015).N-Terminal Modification with Pseudo-Bifunctional PEG-Hexadecane Markedly Improves the Pharmacological Profile of Human Growth Hormone.MOLECULAR PHARMACEUTICS,12(5),1402-1411.
MLA Wu, Ling,et al."N-Terminal Modification with Pseudo-Bifunctional PEG-Hexadecane Markedly Improves the Pharmacological Profile of Human Growth Hormone".MOLECULAR PHARMACEUTICS 12.5(2015):1402-1411.
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