title: Specific targeting of the IL-23 receptor, using a novel small peptide noncompetitive antagonist, decreases the inflammatory response.
abstract: IL-23 is part of the IL-12 family of cytokines and is composed of the p19 subunit specific to IL-23 and the p40 subunit shared with IL-12. IL-23 specifically contributes to the inflammatory process of multiple chronic inflammatory autoimmune disorders, including psoriasis, multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis. So far, one antibody targeting the shared p40 subunit of IL-12 and IL-23, Ustekinumab, is approved clinically to treat psoriasis. However, there are no treatments inhibiting specifically the IL-23 proinflammatory response. We have developed small IL-23R-specific antagonists by designing all D-peptides arising from flexible regions of IL-23R. Of these peptides, we selected 2305 (teeeqqly), since in addition to its soluble properties, it inhibited IL-23-induced STAT3 phosphorylation in spleen cells. Peptide 2305 specifically binds to IL-23R/IL-12Rβ1-expressing HEK-293 cells and not to cells devoid of the receptor. Peptide 2305 showed functional selectivity by modulating IL-23-induced gene expression in IL-23R/IL-12Rβ1-expressing cells and in Jurkat cells; 2305 does not inhibit IL-12-induced cytokine expression in IL-12Rβ-IL-12Rβ2-HEK-293 cells. Finally, compared with anti-p40 treatment, 2305 effectively and selectively inhibits IL-23-induced inflammation in three in vivo mouse models: IL-23-induced ear inflammation, anti-CD40-induced systemic inflammatory response, and collagen-induced arthritis. We, hereby, describe the discovery and characterization of a potent IL-23R small-peptide modulator, 2305 (teeeqqly), that is effective in vivo. 2305 may be more convenient, less cumbersome, less costly, and most importantly, more specific than current biologics for the treatment of inflammatory conditions, and conceivably complement the actual therapies for these chronic and debilitating inflammatory diseases.
authors.affiliation: Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Montréal, Canada;
authors.forename: Christiane
authors.initials: C
authors.lastname: Quiniou
authors.affiliation: Maisonneuve-Rosemont Hospital, Research Center, Montreal, Canada;
authors.forename: Maria
authors.initials: M
authors.lastname: Domínguez-Punaro
authors.affiliation: Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Montréal, Canada;
authors.forename: Frank
authors.initials: F
authors.lastname: Cloutier
authors.affiliation: Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Montréal, Canada;
authors.forename: Atefeh
authors.initials: A
authors.lastname: Erfani
authors.affiliation: Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Montréal, Canada;
authors.forename: Jamila
authors.initials: J
authors.lastname: Ennaciri
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada;
authors.forename: Durgajini
authors.initials: D
authors.lastname: Sivanesan
authors.affiliation: Department of Biochemistry, Université de Montréal, Montréal, Canada;
authors.forename: Mélanie
authors.initials: M
authors.lastname: Sanchez
authors.affiliation: Maisonneuve-Rosemont Hospital, Research Center, Montreal, Canada; Department of Microbiology and Immunology, Université de Montréal, Montréal, Canada;
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Chognard
authors.affiliation: Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Montréal, Canada;
authors.forename: Xin
authors.initials: X
authors.lastname: Hou
authors.affiliation: Maisonneuve-Rosemont Hospital, Research Center, Montreal, Canada;
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Rivera
authors.affiliation: Montreal Heart Institute, Montréal, Canada;
authors.forename: Claudine
authors.initials: C
authors.lastname: Beauchamp
authors.affiliation: Montreal Heart Institute, Montréal, Canada;
authors.forename: Guy
authors.initials: G
authors.lastname: Charron
authors.affiliation: Maisonneuve-Rosemont Hospital, Research Center, Montreal, Canada;
authors.forename: Marie
authors.initials: M
authors.lastname: Vilquin
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Vijay
authors.initials: V
authors.lastname: Kuchroo
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada;
authors.forename: Stephen
authors.initials: S
authors.lastname: Michnick
authors.affiliation: Montreal Heart Institute, Montréal, Canada; Department of Medicine, Université de Montréal, Montréal, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.affiliation: Maisonneuve-Rosemont Hospital, Research Center, Montreal, Canada; Department of Microbiology and Immunology, Université de Montréal, Montréal, Canada;
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lesage
authors.affiliation: Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Montréal, Canada; sylvain.chemtob@umontreal.ca.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D017076:Computer-Aided Design; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D053711:Interleukin-12 Receptor beta 1 Subunit / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008297:Male; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; C515500:IL23R protein, human; D018836:Inflammation Mediators; D053711:Interleukin-12 Receptor beta 1 Subunit; D009842:Oligopeptides; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C528688:interleukin-23 receptor, mouse
keywords: arthritis; cytokine receptors; inflammation; interleukin-23R; peptides