期刊
EMBO MOLECULAR MEDICINE
卷 12, 期 4, 页码 -出版社
WILEY
DOI: 10.15252/emmm.201911621
关键词
drugs; microbial metabolite; mimics; pregnane X receptor; therapy
资金
- ICTR Pilot Award (AECOM)
- Broad Medical Research Program (BMRP) at CCFA (Crohn's & Colitis Foundation of America) [362520]
- NIH [R35 ES028244, HHSN261200800001E, R01 CA207416, CA127231, CA 161879]
- Department of Defense Partnering PI [W81XWH-17-1-0479, PR160167]
- Diabetes Research Center Grant [P30 DK020541]
- Cancer Center Grant [P30CA013330]
- NIH Instrument Award [1S10OD019961-01]
- LTQ Orbitrap Velos Mass Spectrometer System [1S10RR029398]
- NIH CTSA [1 UL1 TR001073]
- Czech Science Foundation [19-00236S]
- Operational Programme Research, Development and Education-European Regional Development Fund, the Ministry of Education, Youth and Sports of the Czech Republic [CZ.02.1.01/0.0/0.0/16_019/0000754]
- National Academy of Sciences, India
- Crohn's Colitis Canada
- Dr. Lloyd Sutherland Investigatorship in IBD/GI Research
- Natural Sciences and Engineering Research Council (NSERC) [RGPIN-2016-03842]
- CIHR
- [ES030197]
- [R43DK105694]
- [P30DK041296]
The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first-in-class non-cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR-specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.
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