2. Academic Validation
  3. Targeting the pregnane X receptor using microbial metabolite mimicry

Targeting the pregnane X receptor using microbial metabolite mimicry

  • EMBO Mol Med. 2020 Apr 7;12(4):e11621. doi: 10.15252/emmm.201911621.
Zdeněk Dvořák # 1,  Felix Kopp # 2,  Cait M Costello 3,  Jazmin S Kemp 3,  Hao Li # 4,  Aneta Vrzalová # 1,  Martina Štěpánková 1,  Iveta Bartoňková 1,  Eva Jiskrová 1,  Karolína Poulíková 1,  Barbora Vyhlídalová 1,  Lars U Nordstroem 2,  Chamini V Karunaratne 2,  Harmit S Ranhotra 4,  Kyu Shik Mun 5,  Anjaparavanda P Naren 5,  Iain A Murray 6,  Gary H Perdew 6,  Julius Brtko 7,  Lucia Toporova 7,  Arne Schön 8,  Bret D Wallace 9,  William G Walton 9,  Matthew R Redinbo 9,  Katherine Sun 10,  Amanda Beck 11,  Sandhya Kortagere 12,  Michelle C Neary 13,  Aneesh Chandran 14,  Saraswathi Vishveshwara 14,  Maria M Cavalluzzi 15,  Giovanni Lentini 15,  Julia Yue Cui 16,  Haiwei Gu 17,  John C March 3,  Shirshendu Chatterjee 18,  Adam Matson 19,  Dennis Wright 20,  Kyle L Flannigan 21,  Simon A Hirota 21,  Ryan Balfour Sartor 22,  Sridhar Mani 4
Affiliations

Affiliations

  • 1 Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic.
  • 2 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 3 The Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA.
  • 4 Department of Medicine, Genetics and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 5 Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 6 Department of Veterinary and Biomedical Sciences, Penn State College of Agricultural Sciences, University Park, PA, USA.
  • 7 Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.
  • 8 The Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
  • 9 Department of Chemistry, University of North Carolina, Chapel Hill, NC, USA.
  • 10 The Department of Pathology, New York University School of Medicine, New York, NY, USA.
  • 11 Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 12 Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA.
  • 13 Department of Chemistry, City University of New York-Hunter College, New York, NY, USA.
  • 14 Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
  • 15 Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Bari, Italy.
  • 16 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
  • 17 Center for Metabolic and Vascular Biology, College of Health Solutions, Arizona State University, Scottsdale, AZ, USA.
  • 18 City University of New York, City College and Graduate Center, New York, NY, USA.
  • 19 Department of Pediatrics and Immunology, University of Connecticut, Farmington, CT, USA.
  • 20 Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA.
  • 21 Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.
  • 22 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.
  • # Contributed equally.
PMID: 32153125 DOI: 10.15252/emmm.201911621
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.

Keywords

drugs; microbial metabolite; mimics; pregnane X receptor; therapy.

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