Reversible PEGylation: a novel technology to release native interferon alpha2 over a prolonged time period

Journal of Medicinal Chemistry
Tal Peleg-ShulmanYoram Shechter

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-IFNalpha2 conjugate, PEG(40)-FMS-IFNalpha2, capable of regenerating native interferon alpha2 (IFNalpha2) 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 IFNalpha2 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 IFNalpha2 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 IFNalpha2 scaled linearly with the quantity injected. Comparing subcutaneous to intravenous administration of PEG(40)-FMS-IFNalpha2, we found that the long circulatory l...Continue Reading

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Citations

Apr 5, 2012·Proceedings of the National Academy of Sciences of the United States of America·Daniel V SantiGary W Ashley
Feb 19, 2008·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Leo G J De LeedeDavid G Spencer
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Sep 22, 2007·Advanced Drug Delivery Reviews·David Filpula, Hong Zhao
Oct 28, 2005·Journal of Molecular Recognition : JMR·Rebecca L Rich, David G Myszka
Oct 30, 2014·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Esther M YooSherie L Morrison
Jan 24, 2015·Bioconjugate Chemistry·Yuhui GongMarc A Gauthier
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Mar 24, 2010·International Journal of Pharmaceutics·Débora da Silva Freitas, José Abrahão-Neto
Oct 6, 2007·Advanced Drug Delivery Reviews·Angelo FontanaFrancesco M Veronese

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