Comparison of Site-Specific PEGylations of the N-Terminus of Interferon Beta-1b: Selectivity, Efficiency, and in Vivo/Vitro Activity

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	Comparison of Site-Specific PEGylations of the N-Terminus of Interferon Beta-1b: Selectivity, Efficiency, and in Vivo/Vitro Activity
	Zhou, Zhan 1,2; Zhang, Jing 1; Sun, Lijing 1; Ma, Guanghui 1; Su, Zhiguo 1
刊名	BIOCONJUGATE CHEMISTRY
	2014
卷号	25 期号:1 页码:138-146
关键词	multiple-sclerosis patients neutralizing antibodies periodate-oxidation combination therapy polyethylene-glycol protein efficacy tolerability stability chemistry
ISSN号	1043-1802
其他题名	Bioconjugate Chem.
中文摘要	PEGylation, including nonspecific and site-directed approaches, is a well-established and validated strategy to increase the stability, in vivo plasma retention time, and efficacy of protein pharmaceutics together with a reduction in immunogenicity and hydrophobicity. Site-directed conjugation by PEG-aldehyde is the most widely used method for N-terminal modification; however, the generation of multimodified products is inevitable because of lysine chemistry, which always leads to difficulties in purification and quantification. In this study, we developed a specific PEGylation strategy through the periodation of the N-terminus of interferon bean) (IFN-beta-1b) followed by the coupling of PEG-hydrazide. The prolonged elimination half-life and significantly diminished immunogenicity of the PEG-hydrazide-modified protein indicated the development of an effective process for improving the pharmacology and immunogenicity of IFN-beta-1b. We further conducted comparisons on the selectivity, velocity, yield, and pharmacokinetics of the two methods. The results demonstrated that the hydrazide-based conjugation was a highly specific coupling reaction that only produced homogeneous N-terminal mono-PEGylated conjugate but also generated heterogeneous multimodified products in the aldehyde-based process. In addition, a better PEGylation yield was found for the hydrazide conjugation compared with that of the aldehyde strategy. These investigations supply a practical approach for the site-specific modification of proteins with an N-terminal serine or threonine to achieve improved homogeneity of the conjugates as well as enhanced pharmacological properties.
英文摘要	PEGylation, including nonspecific and site-directed approaches, is a well-established and validated strategy to increase the stability, in vivo plasma retention time, and efficacy of protein pharmaceutics together with a reduction in immunogenicity and hydrophobicity. Site-directed conjugation by PEG-aldehyde is the most widely used method for N-terminal modification; however, the generation of multimodified products is inevitable because of lysine chemistry, which always leads to difficulties in purification and quantification. In this study, we developed a specific PEGylation strategy through the periodation of the N-terminus of interferon bean) (IFN-beta-1b) followed by the coupling of PEG-hydrazide. The prolonged elimination half-life and significantly diminished immunogenicity of the PEG-hydrazide-modified protein indicated the development of an effective process for improving the pharmacology and immunogenicity of IFN-beta-1b. We further conducted comparisons on the selectivity, velocity, yield, and pharmacokinetics of the two methods. The results demonstrated that the hydrazide-based conjugation was a highly specific coupling reaction that only produced homogeneous N-terminal mono-PEGylated conjugate but also generated heterogeneous multimodified products in the aldehyde-based process. In addition, a better PEGylation yield was found for the hydrazide conjugation compared with that of the aldehyde strategy. These investigations supply a practical approach for the site-specific modification of proteins with an N-terminal serine or threonine to achieve improved homogeneity of the conjugates as well as enhanced pharmacological properties.
WOS标题词	Science & Technology ; Life Sciences & Biomedicine ; Physical Sciences
类目[WOS]	Biochemical Research Methods ; Biochemistry & Molecular Biology ; Chemistry, Multidisciplinary ; Chemistry, Organic
研究领域[WOS]	Biochemistry & Molecular Biology ; Chemistry
关键词[WOS]	MULTIPLE-SCLEROSIS PATIENTS ; NEUTRALIZING ANTIBODIES ; PERIODATE-OXIDATION ; COMBINATION THERAPY ; POLYETHYLENE-GLYCOL ; PROTEIN ; EFFICACY ; TOLERABILITY ; STABILITY ; CHEMISTRY
收录类别	SCI
原文出处	://WOS:000330018400016
语种	英语
WOS记录号	WOS:000330018400016
公开日期	2014-05-06
内容类型	期刊论文
版本	出版稿
源URL	[http://ir.ipe.ac.cn/handle/122111/8059]
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 100049, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Zhan,Zhang, Jing,Sun, Lijing,et al. Comparison of Site-Specific PEGylations of the N-Terminus of Interferon Beta-1b: Selectivity, Efficiency, and in Vivo/Vitro Activity[J]. BIOCONJUGATE CHEMISTRY,2014,25(1):138-146.
APA	Zhou, Zhan,Zhang, Jing,Sun, Lijing,Ma, Guanghui,&Su, Zhiguo.(2014).Comparison of Site-Specific PEGylations of the N-Terminus of Interferon Beta-1b: Selectivity, Efficiency, and in Vivo/Vitro Activity.BIOCONJUGATE CHEMISTRY,25(1),138-146.
MLA	Zhou, Zhan,et al."Comparison of Site-Specific PEGylations of the N-Terminus of Interferon Beta-1b: Selectivity, Efficiency, and in Vivo/Vitro Activity".BIOCONJUGATE CHEMISTRY 25.1(2014):138-146.