Journal article
Targeting the pregnane X receptor using microbial metabolite mimicry
EMBO molecular medicine, v 12(4), pp e11621-n/a
07 Apr 2020
PMID: 32153125
Featured in Collection : UN Sustainable Development Goals @ Drexel
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,
FKK
6 (Felix Kopp Kortagere 6), binds directly to
PXR
protein in solution, induces
PXR
‐specific target gene expression in cells, human organoids, and mice.
FKK
6 significantly represses pro‐inflammatory cytokine production cells and abrogates inflammation in mice expressing the human
PXR
gene. The development of
FKK
6 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.
This study demonstrates that microbial metabolite mimicry can expand the chemical space in drug discovery. Chemical mimics of microbial indoles interacting with a host nuclear receptor provides a novel and non‐toxic therapeutic approach for treating inflammatory conditions of the intestine.
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Details
- Title
- Targeting the pregnane X receptor using microbial metabolite mimicry
- Creators
- Zdeněk Dvořák - Palacký University OlomoucFelix Kopp - Albert Einstein College of MedicineCait M Costello - Cornell UniversityJazmin S Kemp - Cornell UniversityHao Li - Albert Einstein College of MedicineAneta Vrzalová - Palacký University OlomoucMartina Štěpánková - Present addressIveta Bartoňková - Palacký University OlomoucEva Jiskrová - Palacký University OlomoucKarolína Poulíková - Palacký University OlomoucBarbora Vyhlídalová - Palacký University OlomoucLars U Nordstroem - Albert Einstein College of MedicineChamini V Karunaratne - Albert Einstein College of MedicineHarmit S Ranhotra - Albert Einstein College of MedicineKyu Shik Mun - Cincinnati Children's Hospital Medical CenterAnjaparavanda P Naren - Cincinnati Children's Hospital Medical CenterIain A Murray - Pennsylvania State UniversityGary H Perdew - Pennsylvania State UniversityJulius Brtko - Institute of Experimental Endocrinology of the Slovak Academy of SciencesLucia Toporova - Institute of Experimental Endocrinology of the Slovak Academy of SciencesArne Schön - Johns Hopkins UniversityBret D Wallace - University of North Carolina at Chapel HillWilliam G Walton - University of North Carolina at Chapel HillMatthew R Redinbo - University of North Carolina at Chapel HillKatherine Sun - New York UniversityAmanda Beck - Albert Einstein College of MedicineSandhya Kortagere - Drexel UniversityMichelle C Neary - Hunter CollegeAneesh Chandran - Indian Institute of Science BangaloreSaraswathi Vishveshwara - Indian Institute of Science BangaloreMaria M Cavalluzzi - University of Bari Aldo MoroGiovanni Lentini - University of Bari Aldo MoroJulia Yue Cui - University of WashingtonHaiwei Gu - Arizona State UniversityJohn C March - Present addressShirshendu Chatterjee - City University of New YorkAdam Matson - University of ConnecticutDennis Wright - Present addressKyle L Flannigan - University of CalgarySimon A Hirota - University of CalgaryRyan Balfour Sartor - University of North Carolina at Chapel HillSridhar Mani - Albert Einstein College of Medicine
- Publication Details
- EMBO molecular medicine, v 12(4), pp e11621-n/a
- Publisher
- John Wiley and Sons Inc
- Grant note
- ; CA127231; CA 161879 / ; PR160167 / ; P30 DK020541 / Diabetes Research Center Grant ES030197; ES028244 / ; 362520 / ICTR Pilot Award W81XWH-17-1-0479; PR160167 / Department of Defense Partnering PI P30CA013330 / Cancer Center Grant
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000526640800009
- Scopus ID
- 2-s2.0-85081220801
- Other Identifier
- 991020548235604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Medicine, Research & Experimental