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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Autores principales:	Brian Krumm, Xiangzhi Meng, Yan Xiang, Junpeng Deng
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1c88fdede59c408984d6dcc9a8111a5e
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spelling	oai:doaj.org-article:1c88fdede59c408984d6dcc9a8111a5e2021-12-02T12:30:44ZIdentification of small molecule inhibitors of Interleukin-1810.1038/s41598-017-00532-x2045-2322https://doaj.org/article/1c88fdede59c408984d6dcc9a8111a5e2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00532-xhttps://doaj.org/toc/2045-2322Abstract 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.Brian KrummXiangzhi MengYan XiangJunpeng DengNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Brian Krumm Xiangzhi Meng Yan Xiang Junpeng Deng Identification of small molecule inhibitors of Interleukin-18
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.
format	article
author	Brian Krumm Xiangzhi Meng Yan Xiang Junpeng Deng
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 Portfolio
publishDate	2017
url	https://doaj.org/article/1c88fdede59c408984d6dcc9a8111a5e
work_keys_str_mv	AT briankrumm identificationofsmallmoleculeinhibitorsofinterleukin18 AT xiangzhimeng identificationofsmallmoleculeinhibitorsofinterleukin18 AT yanxiang identificationofsmallmoleculeinhibitorsofinterleukin18 AT junpengdeng identificationofsmallmoleculeinhibitorsofinterleukin18
_version_	1718394320444194816

Identification of small molecule inhibitors of Interleukin-18

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