Targeting the pregnane X receptor using microbial metabolite mimicry

. 2020 Apr 07 ; 12 (4) : e11621. [epub] 20200310

Jazyk angličtina Země Německo Médium print-electronic

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem, Research Support, U.S. Gov't, Non-P.H.S.

Perzistentní odkaz   https://www.medvik.cz/link/pmid32153125

Grantová podpora
P01 DK094779 NIDDK NIH HHS - United States
P30 DK041296 NIDDK NIH HHS - United States
R01 ES030197 NIEHS NIH HHS - United States
R35 ES028244 NIEHS NIH HHS - United States
HHSN261200800001C NCI NIH HHS - United States
R01 CA161879 NCI NIH HHS - United States
R01 CA207416 NCI NIH HHS - United States
S10 RR029398 NCRR NIH HHS - United States
P30 CA013330 NCI NIH HHS - United States
HHSN261200800001E NCI NIH HHS - United States
P30 ES007033 NIEHS NIH HHS - United States
R01 CA127231 NCI NIH HHS - United States
UL1 TR001073 NCATS NIH HHS - United States
P30 DK020541 NIDDK NIH HHS - United States
R01 DK080834 NIDDK NIH HHS - United States
R43 DK105694 NIDDK NIH HHS - United States
S10 OD019961 NIH HHS - United States
UL1 TR002556 NCATS NIH HHS - United States

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.

Center for Metabolic and Vascular Biology College of Health Solutions Arizona State University Scottsdale AZ USA

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 Medicine Genetics and Molecular Pharmacology Albert Einstein College of Medicine Bronx NY 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

Department of Veterinary and Biomedical Sciences Penn State College of Agricultural Sciences University Park PA USA

Division of Gastroenterology and Hepatology Department of Medicine Center for Gastrointestinal Biology and Disease University of North Carolina at Chapel Hill Chapel Hill NC USA

Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences Bratislava Slovak Republic

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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