title: Development of a novel noncompetitive antagonist of IL-1 receptor.
abstract: IL-1 is a major proinflammatory cytokine which interacts with the IL-1 receptor I (IL-1RI) complex, composed of IL-1RI and IL-1R accessory protein subunits. Currently available strategies to counter pathological IL-1 signaling rely on a recombinant IL-1 receptor antagonist, which directly competes with IL-1 for its binding site. Presently, there are no small antagonists of the IL-1RI complex. Given this void, we derived 15 peptides from loops of IL-1R accessory protein, which are putative interactive sites with the IL-1RI subunit. In this study, we substantiate the merits of one of these peptides, rytvela (we termed "101.10"), as an inhibitor of IL-1R and describe its properties consistent with those of an allosteric negative modulator. 101.10 (IC(50) approximately 1 nM) blocked human thymocyte proliferation in vitro, and demonstrated robust in vivo effects in models of hyperthermia and inflammatory bowel disease as well as topically in contact dermatitis, superior to corticosteroids and IL-1ra; 101.10 did not bind to IL-1RI deficient cells and was ineffective in vivo in IL-1RI knockout mice. Importantly, characterization of 101.10, revealed noncompetitive antagonist actions and functional selectivity by blocking certain IL-1R pathways while not affecting others. Findings describe the discovery of a potent and specific small (peptide) antagonist of IL-1RI, with properties in line with an allosteric negative modulator.
authors.affiliation: St-Justine Hospital Research Centre, Montreal, Quebec, Canada.
authors.forename: Christiane
authors.initials: C
authors.lastname: Quiniou
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lahaie
authors.forename: Xin
authors.initials: X
authors.lastname: Hou
authors.forename: Sonia
authors.initials: S
authors.lastname: Brault
authors.forename: Martin
authors.initials: M
authors.lastname: Beauchamp
authors.forename: Martin
authors.initials: M
authors.lastname: Leduc
authors.forename: Lenka
authors.initials: L
authors.lastname: Rihakova
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Joyal
authors.forename: Sylvain
authors.initials: S
authors.lastname: Nadeau
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Heveker
authors.forename: William
authors.initials: W
authors.lastname: Lubell
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
authors.forename: Fernand
authors.initials: F
authors.lastname: Gobeil
authors.forename: Greg
authors.initials: G
authors.lastname: Miller
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pshezhetsky
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents; D015153:Blotting, Western; D003872:Dermatitis / Q000188:drug therapy; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D053590:Interleukin 1 Receptor Antagonist Protein; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*
chemical_list: C529594:101.10 peptide; D000893:Anti-Inflammatory Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D010455:Peptides; D017472:Receptors, Interleukin-1