Phenyl Amide Linker Improves the Pharmacokinetics and Pharmacodynamics of N-Terminally Mono-PEGylated Human Growth Hormone
文献类型：期刊论文
| 作者 | Wu, Ling1,2; Ji, Shaoyang1; Shen, Lijuan1; Hu, Tao1 |
| 刊名 | MOLECULAR PHARMACEUTICS
 |
| 出版日期 | 2014-09-01 |
| 卷号 | 11期号:9页码:3080-3089 |
| 关键词 | growth hormone PEGylation pharmacokinetics pharmacodynamics |
| ISSN号 | 1543-8384 |
| 其他题名 | Mol. Pharm. |
| 中文摘要 | 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. |
| 英文摘要 | 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. |
| WOS标题词 | Science & Technology ; Life Sciences & Biomedicine |
| 类目[WOS] | Medicine, Research & Experimental ; Pharmacology & Pharmacy |
| 研究领域[WOS] | Research & Experimental Medicine ; Pharmacology & Pharmacy |
| 关键词[WOS] | FUSION PROTEIN ; DRUG-DELIVERY ; STAPHYLOKINASE ; CHILDREN ; DEFICIENCY ; SECRETION ; GLUCOSE ; SAFETY ; POTENT |
| 收录类别 | SCI |
| 原文出处 | |
| 语种 | 英语 |
| WOS记录号 | WOS:000341230000011 |
| 公开日期 | 2014-09-30 |
| 版本 | 出版稿 |
| 源URL | [http://ir.ipe.ac.cn/handle/122111/11556]  |
| 专题 | 过程工程研究所_研究所（批量导入） |
| 作者单位 | 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 |
| 推荐引用方式 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. |
入库方式： OAI收割
来源：过程工程研究所
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