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ORIGINAL RESEARCH ARTICLE

Characterization of N-Terminal Interferon Mutants: P26L Affords Enhanced Activity and Lack of Toxicity

Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742

To whom requests for reprints should be addressed at ¹ National Institutes of Health, National Center for Complementary and Alternative Medicine, 6707 Democracy Boulevard, Suite 401 Bethesda, MD 20892. Phone: 301-435-6286; Fax: 301-480-2419; E-mail: pontzerc{at}mail.nih.gov

Interferon (IFN)– is a type I IFN that is responsible for the maternal recognition of pregnancy in ruminants. This protein also has classic IFN-like properties, including antiviral, antiproliferative, and immunomodulatory functions. Using IFN- as a model, we examined the structural basis for the activity of type I IFNs, focusing on amino acids within helix A and the first section of the AB loop, which have been proposed as a site for receptor interaction. Six amino-acid substitutions were made that replaced a residue in ovine IFN-1mod with the corresponding residue in human IFN-A. Receptor binding was enhanced by a P26L mutation and was reduced by a conservative lysine-to-histidine substitution at residue 34. Alterations in the antiviral and antiproliferative activities of the IFN- mutants were not always correlated, but both functions were maintained or enhanced relative to the wild-type IFN- by the proline-to-leucine mutation at residue 26. In contrast, this mutation did not affect the low in vitro cytotoxicity that is characteristic of ovine IFN-1mod. Thus, the IFN- P26L mutant may have potential as an improved IFN-based therapeutic.

Key Words: interferon • interferon • antiviral • cytotoxicity • antiproliferative