TY - JOUR
T1 - Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice
AU - Grycová, Aneta
AU - Joo, Hansol
AU - Maier, Vítĕzslav
AU - Illés, Peter
AU - Vyhlídalová, Barbora
AU - Poulíková, Karolína
AU - Sládeková, Lucia
AU - Nádvorník, Petr
AU - Vrzal, Radim
AU - Zemánková, Lenka
AU - Pečinková, Petra
AU - Poruba, Martin
AU - Zapletalová, Iveta
AU - Večeřa, Rostislav
AU - Anzenbacher, Pavel
AU - Ehrmann, Jiří
AU - Ondra, Peter
AU - Jung, Jong Wha
AU - Mani, Sridhar
AU - Dvořák, Zdenĕk
N1 - Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022
Y1 - 2022
N2 - Targeting the aryl hydrocarbon receptor (AhR) is an emerging therapeutic strategy for multiple diseases (e.g., inflammatory bowel disease). Thermosporothrix hazakensis microbial metabolite 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is a putative AhR endogenous ligand. To improve the chemical stability, we synthesized a series of ITE chemical mimics. Using a series of in vitro assays, we identified 2-(1H-indole-3-carbonyl)-N-methyl thiazole-4-carboxamide (ITE-CONHCH3) as a highly potent (EC50 = 1.6 nM) AhR agonist with high affinity (Ki = 88 nM). ITE-CONHCH3 triggered AhR nuclear translocation and dimerization of AhR-ARNT, enhanced AhR binding in the CYP1A1 promoter, and induced AhR-regulated genes in an AhR-dependent manner. The metabolic stability of ITE-CONHCH3 in a cell culture was 10 times higher than that of ITE. Finally, we observed protective effects of ITE-CONHCH3 in mice with DSS-induced colitis. Overall, we demonstrate and validate a concept of microbial metabolite mimicry in the therapeutic targeting of AhR.
AB - Targeting the aryl hydrocarbon receptor (AhR) is an emerging therapeutic strategy for multiple diseases (e.g., inflammatory bowel disease). Thermosporothrix hazakensis microbial metabolite 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is a putative AhR endogenous ligand. To improve the chemical stability, we synthesized a series of ITE chemical mimics. Using a series of in vitro assays, we identified 2-(1H-indole-3-carbonyl)-N-methyl thiazole-4-carboxamide (ITE-CONHCH3) as a highly potent (EC50 = 1.6 nM) AhR agonist with high affinity (Ki = 88 nM). ITE-CONHCH3 triggered AhR nuclear translocation and dimerization of AhR-ARNT, enhanced AhR binding in the CYP1A1 promoter, and induced AhR-regulated genes in an AhR-dependent manner. The metabolic stability of ITE-CONHCH3 in a cell culture was 10 times higher than that of ITE. Finally, we observed protective effects of ITE-CONHCH3 in mice with DSS-induced colitis. Overall, we demonstrate and validate a concept of microbial metabolite mimicry in the therapeutic targeting of AhR.
UR - https://www.scopus.com/pages/publications/85129023942
UR - https://www.scopus.com/pages/publications/85129023942#tab=citedBy
U2 - 10.1021/acs.jmedchem.2c00208
DO - 10.1021/acs.jmedchem.2c00208
M3 - Article
C2 - 35416668
AN - SCOPUS:85129023942
SN - 0022-2623
VL - 65
SP - 6859
EP - 6868
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -