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Development of a Novel Noncompetitive Antagonist of IL-1 Receptor¹

Christiane Quiniou^*, Przemyslaw Sapieha^*, Isabelle Lahaie^*, Xin Hou^*, Sonia Brault^*, Martin Beauchamp^*, Martin Leduc^*, Lenka Rihakova^*, Jean-Sébastien Joyal^*, Sylvain Nadeau^*, Nikolaus Heveker^*, William Lubell, Florian Sennlaub^¶, Fernand Gobeil, Jr., Greg Miller, Alexey V. Pshezhetsky^* and Sylvain Chemtob^2,*

^* St.-Justine Hospital Research Centre, Montreal; Department of Chemistry, University of Montreal, Montreal; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec; Department of Pharmacology, University of Sherbrooke, Sherbrooke, Quebec, Canada; and ^¶ Institut National de la Santé et de la Recherche Médicale, U872, Paris, France

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 (IC₅₀ 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from Valorisation Recherche Québec and the Canadian Institute of Health Research. S.C. is recipient of a Canada Research Chair in perinatology. N.H. is the recipient of a Scientist Award from the Canadian Institute of Health Research. C.Q., P.S., S.B., M.B., M.L., and J.-S.J. are recipients of fellowships/studentships from the Heart and Stroke Foundation of Canada (to C.Q., P.S., and M.L.), Canadian Institutes of Health Research (to S.B. and M.B.), and the Canadian Child Health Clinician Scientist Program-Canadian Institutes of Health Research (to J.-S.J.).

² Address correspondence and reprint requests to Dr. Sylvain Chemtob, St.-Justine Hospital Research Centre, University of Montreal, 3175 Cote-Ste-Catherine, Montreal, Quebec, H3T 1C5 Canada. E-mail address: sylvain.chemtob{at}umontreal.ca

³ Abbreviations used in this paper: IL-1RI, IL-1 receptor type I; IBD, inflammatory bowel disease; BP, blood pressure; TNBS, 2,4,6-trinitrobenzanesulfonic acid; MBP, mean BP.