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Targeting the pregnane X receptor using microbial metabolite mimicry
Z. Dvořák, F. Kopp, CM. Costello, JS. Kemp, H. Li, A. Vrzalová, M. Štěpánková, I. Bartoňková, E. Jiskrová, K. Poulíková, B. Vyhlídalová, LU. Nordstroem, CV. Karunaratne, HS. Ranhotra, KS. Mun, AP. Naren, IA. Murray, GH. Perdew, J. Brtko, L....
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem, Research Support, U.S. Gov't, Non-P.H.S.
Grantová podpora
P01 DK094779
NIDDK NIH HHS - United States
W81XWH-17-1-0479
Department of Defense Partnering PI - International
R35 ES028244
NIEHS NIH HHS - United States
R01 CA127231
NCI NIH HHS - United States
R01 CA161879
NCI NIH HHS - United States
R01 CA207416
NCI NIH HHS - United States
HHSN261200800001C
CCR NIH HHS - United States
HHSN261200800001E
NCI NIH HHS - United States
CA 161879
HHS | NIH | National Cancer Institute (NCI) - International
P30 DK041296
NIDDK NIH HHS - United States
R01 ES030197
NIEHS NIH HHS - United States
CA127231
HHS | NIH | National Cancer Institute (NCI) - International
P30CA013330
Cancer Center Grant - International
PR160167
DOD | United States Army | MEDCOM | Congressionally Directed Medical Research Programs (CDMRP) - International
UL1 TR001073
NCATS NIH HHS - United States
P30 DK020541
NIDDK NIH HHS - United States
ES028244
HHS | NIH | National Institute of Environmental Health Sciences (NIEHS) - International
R01 DK080834
NIDDK NIH HHS - United States
R43 DK105694
NIDDK NIH HHS - United States
362520
ICTR Pilot Award - International
S10 RR029398
NCRR NIH HHS - United States
S10 OD019961
NIH HHS - United States
UL1 TR002556
NCATS NIH HHS - United States
PR160167
Department of Defense Partnering PI - International
ES030197
HHS | NIH | National Institute of Environmental Health Sciences (NIEHS) - International
P30 CA013330
NCI NIH HHS - United States
CCFA (Crohn's & Colitis Foundation of America) - International
Free Medical Journals od 2009
PubMed Central od 2009
Europe PubMed Central od 2009
ProQuest Central od 2009-04-01
Open Access Digital Library od 2009-01-01
Open Access Digital Library od 2009-01-01
Open Access Digital Library od 2009-01-01
Medline Complete (EBSCOhost) od 2011-01-01
Health & Medicine (ProQuest) od 2009-04-01
Wiley-Blackwell Open Access Titles od 2009
ROAD: Directory of Open Access Scholarly Resources od 2008
Odkazy
PubMed
32153125
DOI
10.15252/emmm.201911621
Knihovny.cz E-zdroje
- MeSH
- cytokiny MeSH
- kultivované buňky MeSH
- lidé MeSH
- ligandy MeSH
- molekulární mimikry * MeSH
- myši MeSH
- organoidy MeSH
- pregnanový X receptor chemie MeSH
- střeva MeSH
- zánět MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
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.
Cincinnati Children's Hospital Medical Center Cincinnati OH USA
City University of New York City College and Graduate Center New York NY USA
Department of Biochemistry Albert Einstein College of Medicine Bronx NY USA
Department of Cell Biology and Genetics Palacký University Olomouc Czech Republic
Department of Chemistry City University of New York Hunter College New York NY USA
Department of Chemistry University of North Carolina Chapel Hill NC USA
Department of Environmental and Occupational Health Sciences University of Washington Seattle WA USA
Department of Microbiology and Immunology Drexel University College of Medicine Philadelphia PA USA
Department of Pathology Albert Einstein College of Medicine Bronx NY USA
Department of Pediatrics and Immunology University of Connecticut Farmington CT USA
Department of Pharmaceutical Sciences University of Connecticut Storrs CT USA
Department of Pharmacy Pharmaceutical Sciences University of Bari Aldo Moro Bari Italy
Department of Physiology and Pharmacology University of Calgary Calgary AB Canada
Molecular Biophysics Unit Indian Institute of Science Bangalore India
The Department of Biological and Environmental Engineering Cornell University Ithaca NY USA
The Department of Biology Johns Hopkins University Baltimore MD USA
The Department of Pathology New York University School of Medicine New York NY USA
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