Preparation and Biological Evaluation of a Glycosylated Fusion Interferon Directed to Hepatic Receptors

Cai, Giampiero; Jiang, Mengjung; Zhang, Bo; Zhou, Yaoyuan; Lian-fen, Zhang; Lei, Jianyong; Gu, Xiaosong; Cao, Gaoping; Jin, Jian; Zhang, Rongjun

doi:10.1248/bpb.32.440

Cited by 7 publications

(2 citation statements)

References 13 publications

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“…Inhibiting the cytopathic effect of VSV infection in human (WISH) and bovine (MDBK) cell lines presents two classical methods for studying the anti-viral activity of IFNs [1, 20]. As expected, conventional IFN-α had the highest anti-viral activity of approximately 10 8.9 IU/mg in both systems in our study, which is consistent with previous publications in which test systems were varied within a reasonable range [1, 5, 6].…”

Section: Discussionmentioning

confidence: 99%

Elimination of N-glycosylation by site mutation further prolongs the half-life of IFN-α/Fc fusion proteins expressed in Pichia pastoris

et al. 2016

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BackgroundInterferon (IFN)-α has been commonly used as an antiviral drug worldwide; however, its short half-life in circulation due to its low molecular weight and sensitivity to proteases impacts its efficacy and patient compliance.ResultsIn this study, we present an IgG1 Fc fusion strategy to improve the circulation half-life of IFN-α. Three different forms of IgG1 Fc fragments, including the wild type, aglycosylated homodimer and aglycosylated single chain, were each fused with IFN-α and designated as IFN-α/Fc-WT, IFN-α/Fc-MD, and IFN-α/Fc-SC, respectively. The recombinant proteins were expressed in Pichia pastoris and tested using antiviral and pharmacokinetic assays in comparison with the commercial pegylated-IFN-α (PEG-IFN-α). The in vitro study demonstrated that IFN-α/Fc-SC has the highest antiviral activity, while IFN-α/Fc-WT and IFN-α/Fc-MD exhibited antiviral activities comparable to that of PEG-IFN-α. The in vivo pharmacokinetic assay showed that both IFN-α/Fc-WT and IFN-α/Fc-MD have a longer half-life than PEG-IFN-α in SD rats, but IFN-α/Fc-SC has the shortest half-life among them. Importantly, the circulating half-life of 68.3 h for IFN-α/Fc-MD was significantly longer than those of 38.2 h for IFN-α/Fc-WT and 22.2 h for PEG-IFN-α.ConclusionsThe results demonstrate that the elimination of N-glycosylation by mutation of putative N-glycosylation site further prolongs the half-life of the IFN-α/Fc fusion protein and could present an alternative strategy for extending the half-life of low-molecular-weight proteins expressed by P. pastoris for in vivo studies as well as for future clinical applications.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-016-0601-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Elimination of N-glycosylation by site mutation further prolongs the half-life of IFN-α/Fc fusion proteins expressed in Pichia pastoris

et al. 2016

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“…105,106 Moreover the efficiency of such targeting units has been demonstrated for gene or drug delivery to cultured cells or to animals. [107][108][109][110] Therefore, this strategy has been applied for the targeting of a first Cys-based Cu(I) chelating agent to hepatocytes.…”

Section: Hepatocyte Targetingmentioning

confidence: 99%

Chelation therapy in Wilson's disease: from d-penicillamine to the design of selective bioinspired intracellular Cu(i) chelators

Delangle

Mintz²

2012

Dalton Trans.

123

112

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Wilson's disease is an orphan disease due to copper homeostasis dysfunction. Mutations of the ATP7B gene induces an impaired functioning of a Cu-ATPase, impaired Cu detoxification in the liver and copper overload in the body. Indeed, even though copper is an essential element, which is used as cofactor by many enzymes playing vital roles, it becomes toxic when in excess as it promotes cytotoxic reactions leading to oxidative stress. In this perspective, human copper homeostasis is first described in order to explain the mechanisms promoting copper overload in Wilson's disease. We will see that the liver is the main organ for copper distribution and detoxification in the body. Nowadays this disease is treated life-long by systemic chelation therapy, which is not satisfactory in many cases. Therefore the design of more selective and efficient drugs is of great interest. A strategy to design more specific chelators to treat localized copper accumulation in the liver will then be presented. In particular we will show how bioinorganic chemistry may help in the design of such novel chelators by taking inspiration from the biological copper cell transporters.

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Rational Design of Copper and Iron Chelators to Treat Wilson's Disease and Hemochromatosis

Gateau¹,

Mintz²,

Delangle³

2014

Ligand Design in Medicinal Inorganic Chemistry

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Preparation and Biological Evaluation of a Glycosylated Fusion Interferon Directed to Hepatic Receptors

Cited by 7 publications

References 13 publications

Elimination of N-glycosylation by site mutation further prolongs the half-life of IFN-α/Fc fusion proteins expressed in Pichia pastoris

Elimination of N-glycosylation by site mutation further prolongs the half-life of IFN-α/Fc fusion proteins expressed in Pichia pastoris

Chelation therapy in Wilson's disease: from d-penicillamine to the design of selective bioinspired intracellular Cu(i) chelators

Rational Design of Copper and Iron Chelators to Treat Wilson's Disease and Hemochromatosis

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