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...
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doaj-1c88fdede59c408984d6dcc9a8111a5e2020-12-08T00:23:52ZengNature Publishing GroupScientific Reports2045-23222017-03-01711810.1038/s41598-017-00532-xIdentification of small molecule inhibitors of Interleukin-18Brian Krumm0Xiangzhi Meng1Yan Xiang2Junpeng Deng3Department of Biochemistry and Molecular Biology, Oklahoma State UniversityDepartment of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San AntonioDepartment of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San AntonioDepartment of Biochemistry and Molecular Biology, Oklahoma State UniversityAbstract 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 EC50 of ~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.https://doi.org/10.1038/s41598-017-00532-x |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Brian Krumm Xiangzhi Meng Yan Xiang Junpeng Deng |
spellingShingle |
Brian Krumm Xiangzhi Meng Yan Xiang Junpeng Deng Identification of small molecule inhibitors of Interleukin-18 Scientific Reports |
author_facet |
Brian Krumm Xiangzhi Meng Yan Xiang Junpeng Deng |
author_sort |
Brian Krumm |
title |
Identification of small molecule inhibitors of Interleukin-18 |
title_short |
Identification of small molecule inhibitors of Interleukin-18 |
title_full |
Identification of small molecule inhibitors of Interleukin-18 |
title_fullStr |
Identification of small molecule inhibitors of Interleukin-18 |
title_full_unstemmed |
Identification of small molecule inhibitors of Interleukin-18 |
title_sort |
identification of small molecule inhibitors of interleukin-18 |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-03-01 |
description |
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 EC50 of ~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. |
url |
https://doi.org/10.1038/s41598-017-00532-x |
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