Targeting the pregnane X receptor using microbial metabolite mimicry PMID: 32153125

Target-related Cytokines

2026-09-23

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

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.

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.