title: Fine Tuning of a Type 1 Interferon Antagonist.
abstract: Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and enhanced binding to IFNAR2. Here, we further tune the IFN-1ant by producing three additional antagonists based on IFN-1ant but with altered activity profiles. We show that in all three cases the antiproliferative activity of interferons is blocked and the induction of gene transcription of immunomudolatory and antiproliferative associated genes are substantially decreased. Conversely, each of the new antagonists elicits a different degree of antiviral response, STAT phosphorylation and related gene induction. Two of the new antagonists promote decreased activity in relation to the original IFN-1ant, while one of them promotes increased activity. As we do not know the exact causes of the detrimental effects of IFNs, the four antagonists that were produced and analyzed provide the opportunity to investigate the extent of antagonistic and agonistic activity optimal for a given condition.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Urin
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Levin
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Nanaocha
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Harari
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Gideon
authors.initials: G
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004686:Encephalomyocarditis virus / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
chemical_list: D007370:Interferon Type I; D050505:Mutant Proteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D053633:Receptor, Interferon alpha-beta