| | |  | | | | Record from Web of Science® | | | | | | |
| Site of pegylation and polyethylene glycol molecule size attenuate interferon-alpha antiviral and antiproliferative activities through the JAK/STAT signaling pathway |
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| Author(s): Grace MJ, Lee S, Bradshaw S, Chapman J, Spond J, Cox S, DeLorenzo M, Brassard D, Wylie D, Cannon-Carlson S, Cullen C, Indelicato S, Voloch M, Bordens R |
| Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 280 Issue: 8 Pages: 6327-6336 Published: FEB 25 2005 |
| Times Cited: 28 References: 44 |
| Abstract: Therapeutic pegylated interferon-alphas (IFN-alpha) are mixtures of positional isomers that have been monopegylated at specific sites on the core IFN-alpha molecule. The pegylation results in lower in vitro specific activity associated with the core IFN-a molecule that is related to the site of pegylation and size of polyethylene glycol (PEG) attached. We prepared purified, homogeneous, positional pegylation isomers of IFN-alpha2b that were monopegylated using 5-30-kDa linear PEG molecules attached at 7 primary reactive amino acid residues: Cys(1), His(34), Lys(31), Lys(83), Lys(121), Lys(131), and Lys(134). The isomers were evaluated for STAT translocation and antiviral and antiproliferative activity. The site of pegylation strongly influenced activity relative to an IFN-a2b control. The highest residual activity was observed with the His(34) positional isomers, and the lowest was observed with the Cys(1) positional isomers. The Lys positional isomers demonstrated intermediate activity, with a general order of Lys(134) > Lys(83) similar to Lys(131) similar to Lys(121) > Lys(31). The progressive relationship between decreased activity and increased PEG size suggests that pegylation may interfere with interaction and binding of IFN-alpha to the IFNAR1-IFNAR2 heterodimeric receptor. The higher specific activity associated with the His(34) positional isomer suggests that this site may be favorable for pegylating IFN-alpha2b molecules. |
| Document Type: Article |
| Language: English |
| Reprint Address: Grace, MJ (reprint author), , 1011 Morris Ave, Union, NJ 07083 USA |
Addresses:
1. Schering Plough Res Inst, Union, NJ 07083 USA
2. Aventis Pharmaceut, Bridgewater, NJ 08807 USA |
| Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: 902DT |
| ISSN: 0021-9258 |
| DOI: 10.1074/jbc.M41234200 |
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