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Comparison of Site-Specific PEGylations of the N-Terminus of Interferon Beta-1b: Selectivity, Efficiency, and in Vivo/Vitro Activity
Alternative TitleBioconjugate Chem.
Zhou, Zhan1,2; Zhang, Jing1; Sun, Lijing1; Ma, Guanghui1; Su, Zhiguo1
2014
Source PublicationBIOCONJUGATE CHEMISTRY
ISSN1043-1802
Volume25Issue:1Pages:138-146
AbstractPEGylation, 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.; 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.
KeywordMultiple-sclerosis Patients Neutralizing Antibodies Periodate-oxidation Combination Therapy Polyethylene-glycol Protein Efficacy Tolerability Stability Chemistry
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine ; Physical Sciences
DOI10.1021/bc400435u
URL查看原文
Indexed BySCI
Language英语
WOS KeywordMULTIPLE-SCLEROSIS PATIENTS ; NEUTRALIZING ANTIBODIES ; PERIODATE-OXIDATION ; COMBINATION THERAPY ; POLYETHYLENE-GLYCOL ; PROTEIN ; EFFICACY ; TOLERABILITY ; STABILITY ; CHEMISTRY
WOS Research AreaBiochemistry & Molecular Biology ; Chemistry
WOS SubjectBiochemical Research Methods ; Biochemistry & Molecular Biology ; Chemistry, Multidisciplinary ; Chemistry, Organic
WOS IDWOS:000330018400016
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Cited Times:14[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Version出版稿
Identifierhttp://ir.ipe.ac.cn/handle/122111/8059
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 100049, Peoples R China
Recommended Citation
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.
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