Targeting the pregnane X receptor using microbial metabolite mimicry

Dvořák, Zdeněk and Kopp, Felix and Costello, Cait M and Kemp, Jazmin S and Li, Hao and Vrzalová, Aneta and Štěpánková, Martina and Bartoňková, Iveta and Jiskrová, Eva and Poulíková, Karolína and Vyhlídalová, Barbora and Nordstroem, Lars U and Karunaratne, Chamini V and Ranhotra, Harmit S and Mun, Kyu Shik and Naren, Anjaparavanda P and Murray, Iain A and Perdew, Gary H and Brtko, Julius and Toporova, Lucia and Schön, Arne and Wallace, Bret D and Walton, William G and Redinbo, Matthew R and Sun, Katherine and Beck, Amanda and Kortagere, Sandhya and Neary, Michelle C and Chandran, Aneesh and Vishveshwara, Saraswathi and Cavalluzzi, Maria M and Lentini, Giovanni and Cui, Julia Yue and Gu, Haiwei and March, John C and Chatterjee, Shirshendu and Matson, Adam and Wright, Dennis and Flannigan, Kyle L and Hirota, Simon A and Sartor, Ryan Balfour and Mani, Sridhar (2020) Targeting the pregnane X receptor using microbial metabolite mimicry. In: EMBO Molecular Medicine . ISSN 1757-4676

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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 offtarget 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 PXRspecific 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.

Item Type:	Journal Article
Publication:	EMBO Molecular Medicine
Publisher:	Blackwell Publishing Ltd
Additional Information:	The copyright of this article belongs to Blackwell Publishing Ltd
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	13 Aug 2020 13:05
Last Modified:	13 Aug 2020 13:05
URI:	http://eprints.iisc.ac.in/id/eprint/64938

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