ArticleEMBO molecular medicine2020
Targeting the pregnane X receptor using microbial metabolite mimicry.
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Article in EMBO molecular medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40citing papers in PubMed
9.7field-weighted citation impact, top 1% of its field
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Who cites it
40 citing papers in PubMed, 78 citations in OpenAlex.
- Metabolite mimicry identifies butyrate analogs with select protective functions in the intestinal mucosa.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Pregnane X receptor (NR1I2) deficiency in mice reveals context-dependent regulation of inflammatory homeostasis.Frontiers in immunology · 2026Review
- Cytoplasmic PXR regulates glucose metabolism by binding mRNAs and modulating their stability.Nature structural & molecular biology · 2025Article
- Nuclear receptors in health and disease: signaling pathways, biological functions and pharmaceutical interventions.Signal transduction and targeted therapy · 2025Review
- The role of the gut microbiome in disorders of gut-brain interaction.The FEBS journal · 2025Review
- Unlocking the potential: FKK6 as a microbial mimicry-based therapy for chronic inflammation-associated colorectal cancer in a murine model.The Journal of pharmacology and experimental therapeutics · 2025Article
- Gut microbiota-metabolite interactions in drug-induced liver injury: mechanisms, biomarkers, and therapeutic perspectives.Frontiers in cellular and infection microbiology · 2025Review
- Probing and manipulating the gut microbiome with chemistry and chemical tools.Gut microbiome (Cambridge, England) · 2025Review
- Recent advances in gut microbiota metabolite regulation of hepatic pregnane X receptor.Frontiers in immunology · 2025Review
- PROTAC-mediated activation, rather than degradation, of a nuclear receptor reveals complex ligand-receptor interaction network.Structure (London, England : 1993) · 2024Article
- Computationally-Assisted Discovery and Assignment of a New Class of 6/6/5/5 Fused-Ring Diterpene Acting as Pregnane X Receptor Ligands fromJournal of natural products · 2024Article
- Discrete interplay of gut microbiota L-tryptophan metabolites in host biology and disease.Molecular and cellular biochemistry · 2024Review
- Article
- Mimicry of microbially-derived butyrate reveals templates for potent intestinal epithelial HIF stabilizers.Gut microbes · 2023Article
- Synthesis of Metabolites and Metabolite-like Compounds Using Biocatalytic Systems.Metabolites · 2023Review
- Analysis of metabolites in human gut: illuminating the design of gut-targeted drugs.Journal of cheminformatics · 2023Article
- Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease.World journal of gastroenterology · 2023Review
- Regulation of Nuclear Receptors PXR and CAR by Small Molecules and Signal Crosstalk: Roles in Drug Metabolism and Beyond.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Gut Microbial-Derived Metabolites as Immune Modulators of T Helper 17 and Regulatory T Cells.International journal of molecular sciences · 2023Review
Corrections and comments
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Authors and funding
42 authors at 18 institutions in 6 countries.
Zdeněk Dvořák *Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic.ORCID 0000-0002-3938-3585
Felix Kopp *Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
Cait M CostelloThe Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA.
Jazmin S KempThe Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA.
Hao Li *Department of Medicine, Genetics and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
Aneta Vrzalová *Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic.
Martina ŠtěpánkováDepartment of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic.
Iveta BartoňkováDepartment of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic.
Eva JiskrováDepartment of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic.
Karolína PoulíkováDepartment of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic.
Barbora VyhlídalováDepartment of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic.
Lars U NordstroemDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
Chamini V KarunaratneDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
Harmit S RanhotraDepartment of Medicine, Genetics and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
Kyu Shik MunCincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Anjaparavanda P NarenCincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Iain A MurrayDepartment of Veterinary and Biomedical Sciences, Penn State College of Agricultural Sciences, University Park, PA, USA.
Gary H PerdewDepartment of Veterinary and Biomedical Sciences, Penn State College of Agricultural Sciences, University Park, PA, USA.
Julius BrtkoInstitute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Lucia ToporovaInstitute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Arne SchönThe Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
Bret D WallaceDepartment of Chemistry, University of North Carolina, Chapel Hill, NC, USA.
William G WaltonDepartment of Chemistry, University of North Carolina, Chapel Hill, NC, USA.
Matthew R RedinboDepartment of Chemistry, University of North Carolina, Chapel Hill, NC, USA.
Katherine SunThe Department of Pathology, New York University School of Medicine, New York, NY, USA.
Amanda BeckDepartment of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
Sandhya KortagereDepartment of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA.ORCID 0000-0002-3532-8669
Michelle C NearyDepartment of Chemistry, City University of New York-Hunter College, New York, NY, USA.
Aneesh ChandranMolecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
Saraswathi VishveshwaraMolecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
Maria M CavalluzziDepartment of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Bari, Italy.
Giovanni LentiniDepartment of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Bari, Italy.
Julia Yue CuiDepartment of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
Haiwei GuCenter for Metabolic and Vascular Biology, College of Health Solutions, Arizona State University, Scottsdale, AZ, USA.
John C MarchThe Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA.
Shirshendu ChatterjeeCity University of New York, City College and Graduate Center, New York, NY, USA.
Adam MatsonDepartment of Pediatrics and Immunology, University of Connecticut, Farmington, CT, USA.
Dennis WrightDepartment of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA.
Kyle L FlanniganDepartment of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.
Simon A HirotaDepartment of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.
Ryan Balfour SartorDivision of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Sridhar ManiDepartment of Medicine, Genetics and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.ORCID 0000-0003-4132-6157
Albert Einstein College of Medicine · USPalacký University Olomouc · CZUniversity of North Carolina at Chapel Hill · USCornell University · USCincinnati Children's Hospital Medical Center · USIndian Institute of Science Bangalore · INPennsylvania State University · USSlovak Academy of Sciences · SKUniversity of Bari Aldo Moro · ITUniversity of Calgary · CAUniversity of Connecticut · USArizona State University · USCity University of New York · USDrexel University · USJohns Hopkins University · USNew York University · USThe Graduate Center, CUNY · USUniversity of Washington · US
Funding
WORD PROCESSORP30CA013330 · NCI · YESHIVA UNIVERSITY · PI STEVEN C. ALMO · 1985 to 2026
$111.2MXENOBIOTIC BIOTRANSFORMATION AND DISPOSITIONP30ES007033 · NIEHS · UNIVERSITY OF WASHINGTON · PI Sheela Sathyanarayana · 1995 to 2026
$42.5MTranslational Research CoreP30DK020541 · NIDDK · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI STREAMSON C CHUA · 2015 to 2026
$27.7MCTSA Administrative Supplement for Informatics Core: A novel AI/ML system to predict respiratory failure and ARDS in Covid-19 patientsUL1TR002556 · NCATS · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI KELLER, MARLA J, KIM, MIMI Y · 2018 to 2022
$26.7MSpecial Animal CoreP30DK041296 · NIDDK · YESHIVA UNIVERSITY · PI GUPTA, SANJEEV · 1989 to 2018
$22.9MCore-010UL1TR001073 · NCATS · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI KELLER, MARLA J, SHAMOON, HARRY · 2013 to 2017
$21.3MRole of IL-10 in APC Regulation of Protective vs. Pathogenic T Cell Responses toP01DK094779 · NIDDK · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SARTOR, RYAN B · 2013 to 2023
$17.9MInhibition of an apical cAMP transporter (MRP4) in the gut induces diarrheaR01DK080834 · NIDDK · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · PI Anjaparavanda P Naren · 2009 to 2026
$6.8MActivation of the Ah receptor and epithelial integrityR35ES028244 · NIEHS · PENNSYLVANIA STATE UNIVERSITY, THE · PI PERDEW, GARY H. · 2017 to 2024
$6.2MDevelopmental PBDE exposure, gut microbiome, and diabetesR01ES030197 · NIEHS · UNIVERSITY OF WASHINGTON · PI Julia Yue Cui, Haiwei Gu · 2019 to 2026
$5.0MMicrobiome-Targeted Probes to Eliminate Chemotherapy-Induced GI ToxicityR01CA207416 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI REDINBO, MATTHEW R · 2016 to 2018
$1.7MChemical Modulation of Orphan Nuclear Receptor FunctionR01CA127231 · NCI · ALBERT EINSTEIN COLLEGE OF MEDICINE · PI MANI, SRIDHAR · 2009 to 2014
$1.6MCCR NIH HHS HHSN261200800001CNCATS NIH HHS UL1 TR001073NCATS NIH HHS UL1 TR002556NCI NIH HHS HHSN261200800001ENCI NIH HHS P30 CA013330NCI NIH HHS R01 CA127231NCI NIH HHS R01 CA161879NCI NIH HHS R01 CA207416NCRR NIH HHS S10 RR029398NIDDK NIH HHS P01 DK094779NIDDK NIH HHS P30 DK020541NIDDK NIH HHS P30 DK041296NIDDK NIH HHS R01 DK080834NIDDK NIH HHS R43 DK105694NIEHS NIH HHS P30 ES007033NIEHS NIH HHS R01 ES030197NIEHS NIH HHS R35 ES028244NIH HHS S10 OD019961
Abstract
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.
Indexed as
Molecular MimicryAnimalsCells, CulturedCytokinesHumansInflammationIntestinesLigandsMiceOrganoidsPregnane X ReceptorCytokinesLigandsPregnane X Receptordrugsmicrobial metabolitemimicspregnane X receptortherapy
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