TY - JOUR
T1 - Targeting the pregnane X receptor using microbial metabolite mimicry
AU - Dvořák, Zdeněk
AU - Kopp, Felix
AU - Costello, Cait M.
AU - Kemp, Jazmin S.
AU - Li, Hao
AU - Vrzalová, Aneta
AU - Štěpánková, Martina
AU - Bartoňková, Iveta
AU - Jiskrová, Eva
AU - Poulíková, Karolína
AU - Vyhlídalová, Barbora
AU - Nordstroem, Lars U.
AU - Karunaratne, Chamini V.
AU - Ranhotra, Harmit S.
AU - Mun, Kyu Shik
AU - Naren, Anjaparavanda P.
AU - Murray, Iain A.
AU - Perdew, Gary H.
AU - Brtko, Julius
AU - Toporova, Lucia
AU - Schön, Arne
AU - Wallace, William G.
AU - Walton, William G.
AU - Redinbo, Matthew R.
AU - Sun, Katherine
AU - Beck, Amanda
AU - Kortagere, Sandhya
AU - Neary, Michelle C.
AU - Chandran, Aneesh
AU - Vishveshwara, Saraswathi
AU - Cavalluzzi, Maria M.
AU - Lentini, Giovanni
AU - Cui, Julia Yue
AU - Gu, Haiwei
AU - March, John C.
AU - Chatterjee, Shirshendu
AU - Matson, Adam
AU - Wright, Dennis
AU - Flannigan, Kyle L.
AU - Hirota, Simon A.
AU - Sartor, Ryan Balfour
AU - Mani, Sridhar
N1 - Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2020/4/7
Y1 - 2020/4/7
N2 - 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.
AB - 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.
KW - drugs
KW - microbial metabolite
KW - mimics
KW - pregnane X receptor
KW - therapy
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U2 - 10.15252/emmm.201911621
DO - 10.15252/emmm.201911621
M3 - Article
C2 - 32153125
AN - SCOPUS:85081220801
SN - 1757-4676
VL - 12
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
M1 - e11621
ER -