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| Phenyl Amide Linker Improves the Pharmacokinetics and Pharmacodynamics of N-Terminally Mono-PEGylated Human Growth Hormone | |
| Alternative Title | Mol. Pharm. |
| Wu, Ling1,2; Ji, Shaoyang1; Shen, Lijuan1; Hu, Tao1 | |
| 2014-09-01 | |
| Source Publication | MOLECULAR PHARMACEUTICS
 |
| ISSN | 1543-8384 |
| Volume | 11Issue:9Pages:3080-3089 |
| Abstract | 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.; 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. |
| Keyword | Growth Hormone Pegylation Pharmacokinetics Pharmacodynamics |
| Subtype | Article |
| WOS Headings | Science & Technology ; Life Sciences & Biomedicine |
| DOI | 10.1021/mp500266c |
| URL | 查看原文 |
| Indexed By | SCI |
| Language | 英语 |
| WOS Keyword | FUSION PROTEIN ; DRUG-DELIVERY ; STAPHYLOKINASE ; CHILDREN ; DEFICIENCY ; SECRETION ; GLUCOSE ; SAFETY ; POTENT |
| WOS Research Area | Research & Experimental Medicine ; Pharmacology & Pharmacy |
| WOS Subject | Medicine, Research & Experimental ; Pharmacology & Pharmacy |
| WOS ID | WOS:000341230000011 |
| Citation statistics | |
| Document Type | 期刊论文 |
| Version | 出版稿 |
| Identifier | http://ir.ipe.ac.cn/handle/122111/11556 |
| Collection | 研究所（批量导入） |
| Affiliation | 1.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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| File Name/Size | DocType | Version | Access | License | ||
| Phenyl Amide Linker （1377KB） | 限制开放 | CC BY-NC-SA | Application Full Text | |||
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