EMBO Molecular Medicine (Mar 2020)
Targeting the pregnane X receptor using microbial metabolite mimicry
- Zdeněk Dvořák,
- Felix Kopp,
- Cait M Costello,
- Jazmin S Kemp,
- Hao Li,
- Aneta Vrzalová,
- Martina Štěpánková,
- Iveta Bartoňková,
- Eva Jiskrová,
- Karolína Poulíková,
- Barbora Vyhlídalová,
- Lars U Nordstroem,
- Chamini V Karunaratne,
- Harmit S Ranhotra,
- Kyu Shik Mun,
- Anjaparavanda P Naren,
- Iain A Murray,
- Gary H Perdew,
- Julius Brtko,
- Lucia Toporova,
- Arne Schön,
- Bret D Wallace,
- William G Walton,
- Matthew R Redinbo,
- Katherine Sun,
- Amanda Beck,
- Sandhya Kortagere,
- Michelle C Neary,
- Aneesh Chandran,
- Saraswathi Vishveshwara,
- Maria M Cavalluzzi,
- Giovanni Lentini,
- Julia Yue Cui,
- Haiwei Gu,
- John C March,
- Shirshendu Chatterjee,
- Adam Matson,
- Dennis Wright,
- Kyle L Flannigan,
- Simon A Hirota,
- Ryan Balfour Sartor,
- Sridhar Mani
Affiliations
- Zdeněk Dvořák
- Department of Cell Biology and Genetics, Palacký University
- Felix Kopp
- Department of Biochemistry, Albert Einstein College of Medicine
- Cait M Costello
- The Department of Biological and Environmental Engineering, Cornell University
- Jazmin S Kemp
- The Department of Biological and Environmental Engineering, Cornell University
- Hao Li
- Department of Medicine, Genetics and Molecular Pharmacology, Albert Einstein College of Medicine
- Aneta Vrzalová
- Department of Cell Biology and Genetics, Palacký University
- Martina Štěpánková
- Department of Cell Biology and Genetics, Palacký University
- Iveta Bartoňková
- Department of Cell Biology and Genetics, Palacký University
- Eva Jiskrová
- Department of Cell Biology and Genetics, Palacký University
- Karolína Poulíková
- Department of Cell Biology and Genetics, Palacký University
- Barbora Vyhlídalová
- Department of Cell Biology and Genetics, Palacký University
- Lars U Nordstroem
- Department of Biochemistry, Albert Einstein College of Medicine
- Chamini V Karunaratne
- Department of Biochemistry, Albert Einstein College of Medicine
- Harmit S Ranhotra
- Department of Medicine, Genetics and Molecular Pharmacology, Albert Einstein College of Medicine
- Kyu Shik Mun
- Cincinnati Children's Hospital Medical Center
- Anjaparavanda P Naren
- Cincinnati Children's Hospital Medical Center
- Iain A Murray
- Department of Veterinary and Biomedical Sciences, Penn State College of Agricultural Sciences
- Gary H Perdew
- Department of Veterinary and Biomedical Sciences, Penn State College of Agricultural Sciences
- Julius Brtko
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences
- Lucia Toporova
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences
- Arne Schön
- The Department of Biology, Johns Hopkins University
- Bret D Wallace
- Department of Chemistry, University of North Carolina
- William G Walton
- Department of Chemistry, University of North Carolina
- Matthew R Redinbo
- Department of Chemistry, University of North Carolina
- Katherine Sun
- The Department of Pathology, New York University School of Medicine
- Amanda Beck
- Department of Pathology, Albert Einstein College of Medicine
- Sandhya Kortagere
- Department of Microbiology and Immunology, Drexel University College of Medicine
- Michelle C Neary
- Department of Chemistry, City University of New York‐Hunter College
- Aneesh Chandran
- Molecular Biophysics Unit, Indian Institute of Science
- Saraswathi Vishveshwara
- Molecular Biophysics Unit, Indian Institute of Science
- Maria M Cavalluzzi
- Department of Pharmacy—Pharmaceutical Sciences, University of Bari Aldo Moro
- Giovanni Lentini
- Department of Pharmacy—Pharmaceutical Sciences, University of Bari Aldo Moro
- Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington
- Haiwei Gu
- Center for Metabolic and Vascular Biology, College of Health Solutions, Arizona State University
- John C March
- The Department of Biological and Environmental Engineering, Cornell University
- Shirshendu Chatterjee
- City University of New York, City College and Graduate Center
- Adam Matson
- Department of Pediatrics and Immunology, University of Connecticut
- Dennis Wright
- Department of Pharmaceutical Sciences, University of Connecticut
- Kyle L Flannigan
- Department of Physiology and Pharmacology, University of Calgary
- Simon A Hirota
- Department of Physiology and Pharmacology, University of Calgary
- Ryan Balfour Sartor
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill
- Sridhar Mani
- Department of Medicine, Genetics and Molecular Pharmacology, Albert Einstein College of Medicine
- DOI
- https://doi.org/10.15252/emmm.201911621
- Journal volume & issue
-
Vol. 12,
no. 4
pp. 1 – 19
Abstract
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
