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.
Original language | English (US) |
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Article number | e11621 |
Journal | EMBO Molecular Medicine |
Volume | 12 |
Issue number | 4 |
DOIs | |
State | Published - Apr 7 2020 |
Keywords
- drugs
- microbial metabolite
- mimics
- pregnane X receptor
- therapy
ASJC Scopus subject areas
- Molecular Medicine
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CCDC 1948849: Experimental Crystal Structure Determination
Dvořák, Z. (Contributor), Kopp, F. (Contributor), Costello, C. M. (Contributor), Kemp, J. S. (Contributor), Li, H. (Contributor), Vrzalová, A. (Contributor), Štěpánková, M. (Contributor), Bartoňková, I. (Contributor), Jiskrová, E. (Contributor), Poulíková, K. (Contributor), Vyhlídalová, B. (Contributor), Nordstroem, L. U. (Contributor), Karunaratne, C. V. (Contributor), Ranhotra, H. S. (Contributor), Mun, K. S. (Contributor), Naren, A. P. (Contributor), Murray, I. A. (Contributor), Perdew, G. H. (Contributor), Brtko, J. (Contributor), Toporova, L. (Contributor), Schön, A. (Contributor), Wallace, W. G. (Contributor), Walton, W. G. (Contributor), Redinbo, M. R. (Contributor), Sun, K. (Contributor), Beck, A. (Contributor), Kortagere, S. (Contributor), Neary, M. C. (Contributor), Chandran, A. (Contributor), Vishveshwara, S. (Contributor), Cavalluzzi, M. M. (Contributor), Lentini, G. (Contributor), Cui, J. Y. (Contributor), Gu, H. (Contributor), March, J. C. (Contributor), Chatterjee, S. (Contributor), Matson, A. (Contributor), Wright, D. (Contributor), Flannigan, K. L. (Contributor), Hirota, S. A. (Contributor), Sartor, R. B. (Contributor), Mani, S. (Contributor), Vrzalová, A. (Contributor), Nordstroem, L. U. (Contributor), Chaterjee, S. (Contributor), Balfour Sartor, S. R. (Contributor), Dvořák, Z. (Contributor), Vrzalová, A. (Contributor) & Sartor, R. B. (Contributor), The Cambridge Structural Database, 2020
DOI: 10.5517/ccdc.csd.cc23dy3l, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc23dy3l&sid=DataCite
Dataset
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CCDC 1948848: Experimental Crystal Structure Determination
Dvořák, Z. (Contributor), Kopp, F. (Contributor), Costello, C. M. (Contributor), Kemp, J. S. (Contributor), Li, H. (Contributor), Vrzalová, A. (Contributor), Štěpánková, M. (Contributor), Bartoňková, I. (Contributor), Jiskrová, E. (Contributor), Poulíková, K. (Contributor), Vyhlídalová, B. (Contributor), Nordstroem, L. U. (Contributor), Karunaratne, C. (Contributor), Ranhotra, H. (Contributor), Mun, K. S. (Contributor), Naren, A. P. (Contributor), Murray, I. (Contributor), Perdew, G. H. (Contributor), Brtko, J. (Contributor), Toporova, L. (Contributor), Schon, A. (Contributor), Wallace, W. G. (Contributor), Walton, W. G. (Contributor), Redinbo, M. R. (Contributor), Sun, K. (Contributor), Beck, A. (Contributor), Kortagere, S. (Contributor), Neary, M. C. (Contributor), Chandran, A. (Contributor), Vishveshwara, S. (Contributor), Cavalluzzi, M. M. (Contributor), Lentini, G. (Contributor), Cui, J. Y. (Contributor), Gu, H. (Contributor), March, J. C. (Contributor), Chaterjee, S. (Contributor), Matson, A. (Contributor), Wright, D. (Contributor), Flannigan, K. L. (Contributor), Hirota, S. A. (Contributor), Balfour Sartor, S. R. (Contributor), Mani, S. (Contributor), Vrzalová, A. (Contributor), Nordstroem, L. U. (Contributor), Chatterjee, S. (Contributor), Sartor, R. B. (Contributor), Dvořák, Z. (Contributor), Vrzalová, A. (Contributor) & Sartor, R. B. (Contributor), The Cambridge Structural Database, 2020
DOI: 10.5517/ccdc.csd.cc23dy2k, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc23dy2k&sid=DataCite
Dataset