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• W2034931543 abstract "Many peptide and protein drugs have a short circulatory half-life in vivo. The covalent attachment of polyethylene glycol (PEG) chains (PEGylation) can overcome this deficiency, but pegylated peptides and proteins are often inactive. In this study, we present a novel PEG−IFNα2 conjugate, PEG40-FMS−IFNα2, capable of regenerating native interferon α2 (IFNα2) at a slow rate under physiological conditions. A 2-sulfo-9-fluorenylmethoxycarbonyl (FMS) containing bifunctional reagent, MAL-FMS-NHS, has been synthesized, enabling the linkage of a 40 kDa PEG-SH to IFNα2 through a slowly hydrolyzable bond. By use of a BIAcore binding assay, the in vitro rate of regeneration of native interferon was estimated to have a half-life of 65 h. Following subcutaneous administration to rats and monitoring circulating antiviral activity, active IFNα2 levels peaked at 50 h, with substantial levels still being detected 200 h after administration. This value contrasts with a half-life of about 1 h measured for unmodified interferon. The concentration of active IFNα2 scaled linearly with the quantity injected. Comparing subcutaneous to intravenous administration of PEG40-FMS−IFNα2, we found that the long circulatory lifetime of IFNα2 was affected both by the slow rate of absorption of the PEGylated protein from the subcutaneous volume and by the slow rate of discharge from the PEG in circulation. A numerical simulation of the results was in good agreement with the results observed in vivo. The pharmacokinetic profile of this novel IFNα2 conjugate combines a prolonged maintenance in vivo with the regeneration of active-native IFNα2, ensuring ready access to peripheral tissues and thus an overall advantage over currently used formulations." @default.
• W2034931543 created "2016-06-24" @default.
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• W2034931543 date "2004-08-25" @default.
• W2034931543 modified "2023-09-27" @default.
• W2034931543 title "Reversible PEGylation: A Novel Technology To Release Native Interferon α2 over a Prolonged Time Period" @default.
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• W2034931543 doi "https://doi.org/10.1021/jm0497693" @default.
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