PMID- 28352119
OWN - NLM
STAT- MEDLINE
DCOM- 20180830
LR  - 20181113
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 7
IP  - 1
DP  - 2017 Mar 28
TI  - Identification of small molecule inhibitors of Interleukin-18.
PG  - 483
LID - 10.1038/s41598-017-00532-x [doi]
LID - 483
AB  - 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-gamma in a dose-dependent manner with an EC(50) 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.
FAU - Krumm, Brian
AU  - Krumm B
AD  - Department of Biochemistry and Molecular Biology, Oklahoma State University, 
      Stillwater, OK, 74078, USA. bkrumm@email.unc.edu.
AD  - The University of North Carolina, School of Medicine, Pharmacology, Chapel Hill, 
      North Carolina, 27599, United States. bkrumm@email.unc.edu.
FAU - Meng, Xiangzhi
AU  - Meng X
AD  - 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.
FAU - Xiang, Yan
AU  - Xiang Y
AD  - 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.
FAU - Deng, Junpeng
AU  - Deng J
AD  - Department of Biochemistry and Molecular Biology, Oklahoma State University, 
      Stillwater, OK, 74078, USA. junpeng.deng@okstate.edu.
LA  - eng
GR  - R01 AI079217/AI/NIAID NIH HHS/United States
GR  - R21 AI113539/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170328
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Interleukin-18)
RN  - 0 (Ligands)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Cell Line
MH  - Computer Simulation
MH  - *Drug Discovery
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Interferon-gamma/biosynthesis
MH  - Interleukin-18/*antagonists & inhibitors/*chemistry
MH  - Ligands
MH  - Molecular Docking Simulation
MH  - Molecular Dynamics Simulation
MH  - Protein Binding
MH  - Protein Conformation
MH  - Structure-Activity Relationship
PMC - PMC5428663
COIS- The authors declare that they have no competing interests.
EDAT- 2017/03/30 06:00
MHDA- 2018/08/31 06:00
PMCR- 2017/03/28
CRDT- 2017/03/30 06:00
PHST- 2016/09/26 00:00 [received]
PHST- 2017/03/01 00:00 [accepted]
PHST- 2017/03/30 06:00 [entrez]
PHST- 2017/03/30 06:00 [pubmed]
PHST- 2018/08/31 06:00 [medline]
PHST- 2017/03/28 00:00 [pmc-release]
AID - 10.1038/s41598-017-00532-x [pii]
AID - 532 [pii]
AID - 10.1038/s41598-017-00532-x [doi]
PST - epublish
SO  - Sci Rep. 2017 Mar 28;7(1):483. doi: 10.1038/s41598-017-00532-x.