title: AF12198, a novel low molecular weight antagonist, selectively binds the human type I interleukin (IL)-1 receptor and blocks in vivo responses to IL-1.
abstract: Interleukin-1 (IL-1) -alpha and -beta are potent regulators of inflammatory responses. The naturally occurring interleukin-1 receptor antagonist (IL-1ra) is effective in vitro and in vivo in modulating biological responses to IL-1. We have previously reported the discovery of IL-1 antagonist peptides from the search of phage display libraries. Further characterization of this group of peptides has led to a 15-mer, AF12198, Ac-FEWTPGWYQJYALPL-NH2 (J represents the unnatural amino acid, 2-azetidine-1-carboxylic acid), with both in vitro and in vivo IL-1 antagonist activity. AF12198 selectively binds the human type I IL-1 receptor but not the human type II receptor or the murine type I receptor. In vitro, AF12198 inhibits IL-1-induced IL-8 production by human dermal fibroblasts with a half-maximal inhibition concentration or IC50 of 25 nM and IL-1-induced intercellular adhesion molecule-1 (ICAM-1) expression by endothelial cells with an IC50 of 9 nM. When given as an intravenous infusion to cynomolgus monkeys, AF12198 blocks ex vivo IL-1 induction of IL-6 and down modulates in vivo induction of IL-6. This is the first small molecule to show IL-1 receptor antagonist activity in vivo.
authors.affiliation: Hoechst Marion Roussel, Cincinnati, Ohio 45215, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Akeson
authors.forename: C W
authors.initials: CW
authors.lastname: Woods
authors.forename: L C
authors.initials: LC
authors.lastname: Hsieh
authors.forename: R A
authors.initials: RA
authors.lastname: Bohnke
authors.forename: B L
authors.initials: BL
authors.lastname: Ackermann
authors.forename: K Y
authors.initials: KY
authors.lastname: Chan
authors.forename: J L
authors.initials: JL
authors.lastname: Robinson
authors.forename: S D
authors.initials: SD
authors.lastname: Yanofsky
authors.forename: J W
authors.initials: JW
authors.lastname: Jacobs
authors.forename: R W
authors.initials: RW
authors.lastname: Barrett
authors.forename: T L
authors.initials: TL
authors.lastname: Bowlin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000096:biosynthesis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D051379:Mice; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000378:metabolism; D013045:Species Specificity
chemical_list: C102533:AF 12198; D019040:E-Selectin; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D019151:Peptide Library; D010455:Peptides; D011506:Proteins; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D018799:Intercellular Adhesion Molecule-1