Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 609, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2021.121152
Keywords
PEGylation; Glutathione peroxidase mutant; Antioxidant; Stability; Blood circulation half-life
Categories
Funding
- National Natural Science Foundation of China [31872719]
- Department of Science and Technology of Jilin Province [20180414078GH]
- Jilin Province Development and Reform Commission [2019C013]
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In this study, PEGylation of GPxM was shown to enhance its stability and antioxidant effect, while reducing immunogenicity, potentially broadening its application as an important antioxidant drug. The improvement of PEGylated GPxM, especially PEGylated GPx1M, was stronger than that of monoPEGylated GPxM.
Human glutathione peroxidase (GPx), as an important kind of antioxidant enzyme, is often used for the removal of reactive oxygen species. Unfortunately, the application has been hindered by its limited source and poor stability. To solve these problems, human glutathione peroxidase mutant (GPxM) with high activity and yield was obtained using Escherichia coli BL21(DE3) cys auxotrophic strain and the single-protein production system in our previous work. However, the antioxidant effect of this novel recombinant protein drug in animals has not been demonstrated, and its immunogenicity and short biological half-life as a biological macromolecule may have seriously hindered its clinical application. Therefore, it is important to find an effective strategy to address the above issues. In this work, PEGylated GPxM was prepared by conjugating the corresponding mutant with monomethoxy polyethylene glycol succinimidyl succinate (SS-mPEG). We researched the structure, stability, pharmacokinetic properties, antioxidant effect in vivo and protective mechanism against adriamycin (ADR)mediated cardiotoxicity of modified products, and compared with the above properties of GPxM. The results revealed that GPxM had an excellent antioxidant effect in vivo, and PEGylation can enhance the stability, half-life and antioxidant effect of GPxM while reducing immunogenicity. In addition, the above improvement of PEGylated GPx1M was stronger than that of monoPEGylated GPx4M. Hence, PEGylation might be an effective method to broaden the applications of GPxM as the important antioxidant drug, especially the PEGylated GPx1M with high antioxidant effect.
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