title: Lipidization of human interferon-alpha: a new approach toward improving the delivery of protein drugs.
abstract: Human interferon-alpha (IFN-alpha), a 19.2 KD protein containing two disulfide bonds (cys1-cys98; cys29-cys138), was reduced and modified with a reversible lipidization agent. The product of the lipidization, PAL-IFN, was homogenous, with four palmitoyl moieties linked to the four Cys residues in the protein molecule via reversible disulfide linkages. The far-UV circular dichroism (CD) spectrum of PAL-IFN was virtually overlapped with that of IFN, indicating that the IFN structure was not altered by the modification. After iv injection in mice of 0.1 mg/kg of PAL-IFN, a low level of serum IFN activity was sustained for more than 8 h, while serum IFN activity was rapidly diminished to an undetectable level at 2 h post IFN injection at the same dose. Evidence suggested that IFN was slowly released from PAL-IFN into blood circulation upon reduction of the disulfide bonds in vivo. Furthermore, the liver-targeting effect of PAL-IFN was demonstrated by the observation that the level of 2'-5' oligoadenylate synthetase (OAS) expressed in the liver of mice treated with PAL-IFN was significantly higher than that with IFN. In conclusion, reversible lipidization can potentially achieve both a prolonged plasma half-life and an enhanced liver-targeting effect of IFN in antiviral therapy.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern, California, Los Angeles, CA 90089, USA.
authors.forename: Liyun
authors.initials: L
authors.lastname: Yuan
authors.forename: Jeff
authors.initials: J
authors.lastname: Wang
authors.forename: Wei-Chiang
authors.initials: WC
authors.lastname: Shen
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D003692:Delayed-Action Preparations; D004339:Drug Compounding; D004790:Enzyme Induction; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D016898:Interferon-alpha / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D010168:Palmitates / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D053719:Tandem Mass Spectrometry; D013678:Technology, Pharmaceutical / Q000379:methods; D014018:Tissue Distribution
chemical_list: D000998:Antiviral Agents; D003692:Delayed-Action Preparations; D016898:Interferon-alpha; D010168:Palmitates; D015088:2',5'-Oligoadenylate Synthetase