title: Identification of small molecule inhibitors of Interleukin-18.
abstract: Interleukin-18 (IL-18) is a pleiotropic pro-inflammatory cytokine belonging to the IL-1 superfamily. IL-18 plays an important role in host innate and adaptive immune defense but its aberrant activities are also associated with inflammatory diseases such as rheumatoid arthritis and Crohn's disease. IL-18 activity is modulated in vivo by its naturally occurring antagonist, IL-18 Binding Protein (IL-18BP). Recent crystal structures of human IL-18 (hIL-18) in complex with its antagonists or cognate receptor(s) have revealed a conserved binding interface on hIL-18. Through virtual screening of the National Cancer Institute Diversity Set II and in vitro competitive ELISA we have identified three compounds (NSC201631, NSC80734, and NSC61610) that disrupt hIL-18 binding to the ectromelia virus IL-18BP. Through cell-based bioassay, we show that NSC80734 inhibits IL-18-induced production of IFN-γ in a dose-dependent manner with an EC50of ~250 nM. Our results and methodology presented here demonstrate the feasibility of developing small molecule inhibitors that specifically target the rather large interface of IL-18 that is involved in extensive protein-protein interactions with both IL-18BP and its cognate receptor(s). Our data therefore provide the basis for an approach by which small molecules can be identified that modulate IL-18 activity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK, 74078, USA. bkrumm@email.unc.edu.|The University of North Carolina, School of Medicine, Pharmacology, Chapel Hill, North Carolina, 27599, United States. bkrumm@email.unc.edu.
authors.forename: Brian
authors.initials: B
authors.lastname: Krumm
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA.
authors.forename: Xiangzhi
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK, 74078, USA. junpeng.deng@okstate.edu.
authors.forename: Junpeng
authors.initials: J
authors.lastname: Deng
mesh_terms: D002460:Cell Line; D003198:Computer Simulation; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D020382:Interleukin-18; D008024:Ligands; D007371:Interferon-gamma