Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice

Aneta Grycová; Hansol Joo; Vítĕzslav Maier; Peter Illés; Barbora Vyhlídalová; Karolína Poulíková; Lucia Sládeková; Petr Nádvorník; Radim Vrzal; Lenka Zemánková; Petra Pečinková; Martin Poruba; Iveta Zapletalová; Rostislav Večeřa; Pavel Anzenbacher; Jiří Ehrmann; Peter Ondra; Jong Wha Jung; Sridhar Mani; Zdenĕk Dvořák

doi:10.1021/acs.jmedchem.2c00208

Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice

Aneta Grycová, Hansol Joo, Vítĕzslav Maier, Peter Illés, Barbora Vyhlídalová, Karolína Poulíková, Lucia Sládeková, Petr Nádvorník, Radim Vrzal, Lenka Zemánková, Petra Pečinková, Martin Poruba, Iveta Zapletalová, Rostislav Večeřa, Pavel Anzenbacher, Jiří Ehrmann, Peter Ondra, Jong Wha Jung, Sridhar Mani, Zdenĕk Dvořák

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Abstract

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 (K_i = 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.

Original language	English
Pages (from-to)	6859-6868
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	9
DOIs	https://doi.org/10.1021/acs.jmedchem.2c00208
State	Published - 2022

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Grycová, A., Joo, H., Maier, V., Illés, P., Vyhlídalová, B., Poulíková, K., Sládeková, L., Nádvorník, P., Vrzal, R., Zemánková, L., Pečinková, P., Poruba, M., Zapletalová, I., Večeřa, R., Anzenbacher, P., Ehrmann, J., Ondra, P., Jung, J. W., Mani, S., & Dvořák, Z. (2022). Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice. Journal of Medicinal Chemistry, 65(9), 6859-6868. https://doi.org/10.1021/acs.jmedchem.2c00208

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title = "Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice",

abstract = "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.",

author = "Aneta Grycov{\'a} and Hansol Joo and V{\'i}tĕzslav Maier and Peter Ill{\'e}s and Barbora Vyhl{\'i}dalov{\'a} and Karol{\'i}na Poul{\'i}kov{\'a} and Lucia Sl{\'a}dekov{\'a} and Petr N{\'a}dvorn{\'i}k and Radim Vrzal and Lenka Zem{\'a}nkov{\'a} and Petra Pe{\v c}inkov{\'a} and Martin Poruba and Iveta Zapletalov{\'a} and Rostislav Ve{\v c}e{\v r}a and Pavel Anzenbacher and Ji{\v r}{\'i} Ehrmann and Peter Ondra and Jung, {Jong Wha} and Sridhar Mani and Zdenĕk Dvo{\v r}{\'a}k",

note = "Publisher Copyright: {\textcopyright} 2022 American Chemical Society.",

year = "2022",

doi = "10.1021/acs.jmedchem.2c00208",

language = "English",

volume = "65",

pages = "6859--6868",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

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Grycová, A, Joo, H, Maier, V, Illés, P, Vyhlídalová, B, Poulíková, K, Sládeková, L, Nádvorník, P, Vrzal, R, Zemánková, L, Pečinková, P, Poruba, M, Zapletalová, I, Večeřa, R, Anzenbacher, P, Ehrmann, J, Ondra, P, Jung, JW, Mani, S & Dvořák, Z 2022, 'Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice', Journal of Medicinal Chemistry, vol. 65, no. 9, pp. 6859-6868. https://doi.org/10.1021/acs.jmedchem.2c00208

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

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 - http://www.scopus.com/inward/record.url?scp=85129023942&partnerID=8YFLogxK

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 -

Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice

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