PEGylation is effective in reducing immunogenicity, immunotoxicity, and hepatotoxicity of α-momorcharin<i>in vivo</i>

Zheng, Jie; Lei, Ning; He, Qianchuan; Hu, Wei; Jin, Ja-Gui; Meng, Yao; Deng, Ning; Yan-fa, Meng; Zhang, Chongjie; Shen, Fubing

doi:10.3109/08923973.2012.666979

Cited by 36 publications

(29 citation statements)

References 24 publications

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“…There are also reports that RIPs can cause hepatotoxicity in rodents (Tennekoon et al, 1994;Basch et al, 2003). Our long-term toxicity experiments on type I RIPs showed that a-MMC not only have strong immunogenicity and hypersensitivity but also have high hepatotoxicity and lymphocytotoxicity, such as the abnormal liver function and lymphopenia, and the histopathologically diffuse punctate necrosis of hepatocytes and the dissolution of marrow lymphocyte Zheng et al, 2012).…”

Section: Introductionmentioning

confidence: 87%

Cytotoxicity mechanism of α-MMC in normal liver cells through LRP1 mediated endocytosis and JNK activation

Shen

Zhang

et al. 2016

Toxicology

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Section: Introductionmentioning

confidence: 87%

Cytotoxicity mechanism of α-MMC in normal liver cells through LRP1 mediated endocytosis and JNK activation

Shen

Zhang

et al. 2016

Toxicology

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“…The therapeutic potency is improved by increasing serum half-life, decreasing immunogenicity, and reducing renal clearance and proteolytic degradation of the protein [3]–[5]. Typically, a therapeutic protein is conjugated with PEG via a covalent linkage at some reactive moieties of the protein.…”

Section: Introductionmentioning

confidence: 99%

Molecular Insight into the Steric Shielding Effect of PEG on the Conjugated Staphylokinase: Biochemical Characterization and Molecular Dynamics Simulation

2013

PLoS ONE

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PEGylation is a successful approach to improve potency of a therapeutic protein. The improved therapeutic potency is mainly due to the steric shielding effect of PEG. However, the underlying mechanism of this effect on the protein is not well understood, especially on the protein interaction with its high molecular weight substrate or receptor. Here, experimental study and molecular dynamics simulation were used to provide molecular insight into the interaction between the PEGylated protein and its receptor. Staphylokinase (Sak), a therapeutic protein for coronary thrombolysis, was used as a model protein. Four PEGylated Saks were prepared by site-specific conjugation of 5 kDa/20 kDa PEG to N-terminus and C-terminus of Sak, respectively. Experimental study suggests that the native conformation of Sak is essentially not altered by PEGylation. In contrast, the bioactivity, the hydrodynamic volume and the molecular symmetric shape of the PEGylated Sak are altered and dependent on the PEG chain length and the PEGylation site. Molecular modeling of the PEGylated Saks suggests that the PEG chain remains highly flexible and can form a distinctive hydrated layer, thereby resulting in the steric shielding effect of PEG. Docking analyses indicate that the binding affinity of Sak to its receptor is dependent on the PEG chain length and the PEGylation site. Computational simulation results explain experimental data well. Our present study clarifies molecular details of PEG chain on protein surface and may be essential to the rational design, fabrication and clinical application of PEGylated proteins.

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“…A high level of anti-MAP30 IgG was detected at a dose 0.42 mg/kg, while when a lower dose of 0.14 mg/kg was used, a high level of anti-MAP30 IgG was only seen during weeks 3 and 4. Chemical modification by dextran or polyethylene glycol (PEG) has been employed to reduce the immunogenicity of RIPs (Zheng et al 2012; He et al 1999; Chan et al 1999). Recently, a study by (Meng et al 2012b) demonstrated that PEGylated MAP30 has a lower immunogenicity, which may prolong its half-life in vivo.…”

Section: Discussionmentioning

confidence: 99%

Novel purification method and antibiotic activity of recombinant Momordica charantia MAP30

et al. 2017

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Ribosome-inactivating proteins (RIPs) are a group of enzymes originally isolated from plants that possess the ability to damage ribosomes in an irreversible manner, leading to inhibition of protein synthesis in eukaryotic cells. In this study, we aimed to purify recombinant RIPs, investigate their function in the treatment of bacterial infection, and determine their toxicity in mice. We employed a pMAL protein fusion and purification system using E. coli transformed with a plasmid containing MBP-tagged MAP30 cDNA. MBP-tagged MAP30 was purified using a modified novel protocol to effectively produce highly active MAP30 of high purity. In an acute toxicity study in mice, no mortality occurred at doses lower than 1.25 mg/kg. MAP30 at both 0.42 and 0.14 mg/kg induced anti-MAP30 IgG, which reached a maximum titer at week 3. In conclusion, recombinant MAP30 prepared using our purification method possesses bioactivity, and has a synergistic bacteria-killing effect that can significantly reduce the required dosages of chloramphenicol and erythromycin. Therefore, when MAP30 is used in combination with chloramphenicol or erythromycin, it may of benefit in terms of reducing the side effects of the antibiotics, as lower concentrations of antibiotics are required.

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PEGylation is effective in reducing immunogenicity, immunotoxicity, and hepatotoxicity of α-momorcharinin vivo

Abstract: PEGylation is effective in reducing the immunogenicity, immunotoxicity, and hepatotoxicity of α-MMC in vivo.

Cited by 36 publications

References 24 publications

Cytotoxicity mechanism of α-MMC in normal liver cells through LRP1 mediated endocytosis and JNK activation

Cytotoxicity mechanism of α-MMC in normal liver cells through LRP1 mediated endocytosis and JNK activation

Molecular Insight into the Steric Shielding Effect of PEG on the Conjugated Staphylokinase: Biochemical Characterization and Molecular Dynamics Simulation

Novel purification method and antibiotic activity of recombinant Momordica charantia MAP30

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