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Phenyl Amide Linker Improves the Pharmacokinetics and Pharmacodynamics of N-Terminally Mono-PEGylated Human Growth Hormone
Alternative TitleMol. Pharm.
Wu, Ling1,2; Ji, Shaoyang1; Shen, Lijuan1; Hu, Tao1
2014-09-01
Source PublicationMOLECULAR PHARMACEUTICS
ISSN1543-8384
Volume11Issue:9Pages:3080-3089
AbstractHuman growth hormone (hGH) suffers from a short plasma half-life of similar to 15 min, necessitating frequent injections to maintain its physiological effect. PEGylation, conjugation of polyethylene glycol (PEG), is an effective strategy to prolong the plasma half-life of hGH. However, PEGylation can significantly decrease the bioactivity of hGH. Thus, a new PEGylation approach is desired to improve the pharmacokinetics (PK) and pharmacodynamics (PD) of the PEGylated hGH. In the present study, two N-terminally mono-PEGylated hGHs were prepared using aldehyde chemistry. Phenyl amide and ethyl moieties were used as the linkers between PEG and hGH, respectively. The hydrodynamic volume, proteolytic sensitivity, and immunogenicity of the PEGylated hGH with phenyl amide linker (hGH-phenyl-PEG) were lower than those of the one with propyl linker (hGH-prop-PEG). In addition, hGH-phenyl-PEG showed a higher in vitro bioactivity and better PK and PD than hGH-prop-PEG. The better PK of hGH-phenyl-PEG was mainly due to its lower proteolytic sensitivity and low immunogenicity. The better PD of hGH-phenyl-PEG was mainly due to its higher in vitro bioactivity. Thus, the phenyl amide linker can improve the overall pharmacological profiles of the PEGylated hGH. Our study is expected to advance the development of long-acting protein biotherapeutics with high therapeutic efficacy.; Human growth hormone (hGH) suffers from a short plasma half-life of similar to 15 min, necessitating frequent injections to maintain its physiological effect. PEGylation, conjugation of polyethylene glycol (PEG), is an effective strategy to prolong the plasma half-life of hGH. However, PEGylation can significantly decrease the bioactivity of hGH. Thus, a new PEGylation approach is desired to improve the pharmacokinetics (PK) and pharmacodynamics (PD) of the PEGylated hGH. In the present study, two N-terminally mono-PEGylated hGHs were prepared using aldehyde chemistry. Phenyl amide and ethyl moieties were used as the linkers between PEG and hGH, respectively. The hydrodynamic volume, proteolytic sensitivity, and immunogenicity of the PEGylated hGH with phenyl amide linker (hGH-phenyl-PEG) were lower than those of the one with propyl linker (hGH-prop-PEG). In addition, hGH-phenyl-PEG showed a higher in vitro bioactivity and better PK and PD than hGH-prop-PEG. The better PK of hGH-phenyl-PEG was mainly due to its lower proteolytic sensitivity and low immunogenicity. The better PD of hGH-phenyl-PEG was mainly due to its higher in vitro bioactivity. Thus, the phenyl amide linker can improve the overall pharmacological profiles of the PEGylated hGH. Our study is expected to advance the development of long-acting protein biotherapeutics with high therapeutic efficacy.
KeywordGrowth Hormone Pegylation Pharmacokinetics Pharmacodynamics
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
DOI10.1021/mp500266c
URL查看原文
Indexed BySCI
Language英语
WOS KeywordFUSION PROTEIN ; DRUG-DELIVERY ; STAPHYLOKINASE ; CHILDREN ; DEFICIENCY ; SECRETION ; GLUCOSE ; SAFETY ; POTENT
WOS Research AreaResearch & Experimental Medicine ; Pharmacology & Pharmacy
WOS SubjectMedicine, Research & Experimental ; Pharmacology & Pharmacy
WOS IDWOS:000341230000011
Citation statistics
Cited Times:10[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Version出版稿
Identifierhttp://ir.ipe.ac.cn/handle/122111/11556
Collection研究所(批量导入)
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,Shen, Lijuan,et al. Phenyl Amide Linker Improves the Pharmacokinetics and Pharmacodynamics of N-Terminally Mono-PEGylated Human Growth Hormone[J]. MOLECULAR PHARMACEUTICS,2014,11(9):3080-3089.
APA Wu, Ling,Ji, Shaoyang,Shen, Lijuan,&Hu, Tao.(2014).Phenyl Amide Linker Improves the Pharmacokinetics and Pharmacodynamics of N-Terminally Mono-PEGylated Human Growth Hormone.MOLECULAR PHARMACEUTICS,11(9),3080-3089.
MLA Wu, Ling,et al."Phenyl Amide Linker Improves the Pharmacokinetics and Pharmacodynamics of N-Terminally Mono-PEGylated Human Growth Hormone".MOLECULAR PHARMACEUTICS 11.9(2014):3080-3089.
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