Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure-activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure-activity relationships (SAR) between indole mimics and receptors, PXR and AhR.

Department of Anatomy and Structural Biology Albert Einstein College of Medicine Bronx NY USA

Department of Biochemistry Albert Einstein College of Medicine Bronx NY USA

Department of Cell Biology and Genetics Faculty of Science Palacký University Šlechtitelů 27 783 71 Olomouc Czech Republic

Department of Medical Education Albert Einstein College of Medicine Bronx NY USA

Department of Medicine and Genetics Albert Einstein College of Medicine Bronx NY USA

Department of Pathology Albert Einstein College of Medicine Bronx NY USA

Department of Pathology Albert Einstein College of Medicine Bronx NY USA; Department of Pathology University of Chicago Chicago IL USA

Shanghai University of Traditional Chinese Medicine Shanghai China

Zobrazit více v PubMed

Lehmann JM, et al., The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest, 1998. 102(5): p. 1016–23. PubMed PMC

Yu X, et al., Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI. Sci Transl Med, 2020. 12(543). PubMed

Pulakazhi Venu VK, et al., The pregnane X receptor and its microbiota-derived ligand indole 3-propionic acid regulate endothelium-dependent vasodilation. Am J Physiol Endocrinol Metab, 2019. 317(2): p. E350–E361. PubMed PMC

Jain S, et al., Pregnane X Receptor and P-glycoprotein: a connexion for Alzheimer’s disease management. Mol Divers, 2014. 18(4): p. 895–909. PubMed

Cheng J, Shah YM, and Gonzalez FJ, Pregnane X receptor as a target for treatment of inflammatory bowel disorders. Trends Pharmacol Sci, 2012. 33(6): p. 323–30. PubMed PMC

Chai SC, Wright WC, and Chen T, Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer. Med Res Rev, 2020. 40(3): p. 1061–1083. PubMed PMC

Hukkanen J, Hakkola J, and Rysa J, Pregnane X receptor (PXR)--a contributor to the diabetes epidemic? Drug Metabol Drug Interact, 2014. 29(1): p. 3–15. PubMed

Venkatesh M, et al., Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity, 2014. 41(2): p. 296–310. PubMed PMC

Squires EJ, Sueyoshi T, and Negishi M, Cytoplasmic Localization of Pregnane X Receptor and Ligand-dependent Nuclear Translocation in Mouse Liver. Journal of Biological Chemistry, 2004. 279(47): p. 49307–49314. PubMed

Chadha N. and Silakari O, Indoles as therapeutics of interest in medicinal chemistry: Bird’s eye view. Eur J Med Chem, 2017. 134: p. 159–184. PubMed

Ratajewski M, et al., Screening of a chemical library reveals novel PXR-activating pharmacologic compounds. Toxicol Lett, 2015. 232(1): p. 193–202. PubMed

Shukla SJ, et al., Identification of clinically used drugs that activate pregnane X receptors. Drug Metab Dispos, 2011. 39(1): p. 151–9. PubMed PMC

Dring AM, et al., Rational quantitative structure-activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligands. Chem Biol Interact, 2010. 188(3): p. 512–25. PubMed PMC

Pondugula SR, et al., Diindolylmethane, a naturally occurring compound, induces CYP3A4 and MDR1 gene expression by activating human PXR. Toxicol Lett, 2014. 232(3): p. 580–589. PubMed PMC

Wilson A, et al., Attenuation of bile acid-mediated FXR and PXR activation in patients with Crohn’s disease. Sci Rep, 2020. 10(1): p. 1866. PubMed PMC

Ding X, et al., Tryptophan Metabolism, Regulatory T Cells, and Inflammatory Bowel Disease: A Mini Review. Mediators Inflamm, 2020. 2020: p. 9706140. PubMed PMC

Huhn M, et al., Inflammation-Induced Mucosal KYNU Expression Identifies Human Ileal Crohn’s Disease. J Clin Med, 2020. 9(5). PubMed PMC

Little M, et al., Understanding the Physiological Functions of the Host Xenobiotic-sensing Nuclear Receptors PXR and CAR on the Gut Microbiome using Genetically Modified Mice. BMC Preprint (Research Square), 2020. PubMed PMC

Dvorak Z, et al., Weak Microbial Metabolites: a Treasure Trove for Using Biomimicry to Discover and Optimize Drugs. Mol Pharmacol, 2020. 98(4): p. 343–349. PubMed PMC

Illes P, et al., Indole microbial intestinal metabolites expand the repertoire of ligands and agonists of the human pregnane X receptor. Toxicol Lett, 2020. 334: p. 87–93. PubMed

Dvorak Z, et al., Targeting the pregnane X receptor using microbial metabolite mimicry. EMBO Mol Med, 2020. 12(4): p. e11621. PubMed PMC

Novotna A, Pavek P, and Dvorak Z, Novel stably transfected gene reporter human hepatoma cell line for assessment of aryl hydrocarbon receptor transcriptional activity: construction and characterization. Environ Sci Technol, 2011. 45(23): p. 10133–9. PubMed

Vyhlidalova B, et al., Differential activation of human pregnane X receptor PXR by isomeric mono-methylated indoles in intestinal and hepatic in vitro models. Toxicol Lett, 2020. 324: p. 104–110. PubMed

Magro F, et al., European consensus on the histopathology of inflammatory bowel disease. J Crohns Colitis, 2013. 7(10): p. 827–51. PubMed

Feakins RM, Inflammatory bowel disease biopsies: updated British Society of Gastroenterology reporting guidelines. J Clin Pathol, 2013. 66(12): p. 1005–26. PubMed

Cervenka I, Agudelo LZ, and Ruas JL, Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science, 2017. 357(6349). PubMed

Zhang LS and Davies SS, Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions. Genome Med, 2016. 8(1): p. 46. PubMed PMC

Fernstrom JD, A Perspective on the Safety of Supplemental Tryptophan Based on Its Metabolic Fates. J Nutr, 2016. 146(12): p. 2601s–2608s. PubMed

Lamas B, et al., CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med, 2016. 22(6): p. 598–605. PubMed PMC

Rothhammer V, et al., Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med, 2016. 22(6): p. 586–97. PubMed PMC

Mani S, Indole microbial metabolites: expanding and translating target(s). Oncotarget, 2017. 8(32): p. 52014–52015. PubMed PMC

Ranhotra HS, et al., Xenobiotic Receptor-Mediated Regulation of Intestinal Barrier Function and Innate Immunity. Nucl Receptor Res, 2016. 3. PubMed PMC

Brave M, Lukin DJ, and Mani S, Microbial control of intestinal innate immunity. Oncotarget, 2015. 6(24): p. 19962–3. PubMed PMC

Blokzijl H, et al., Decreased P-glycoprotein (P-gp/MDR1) expression in inflamed human intestinal epithelium is independent of PXR protein levels. Inflamm Bowel Dis, 2007. 13(6): p. 710–20. PubMed

Yokobori K, et al., Intracellular localization of pregnane X receptor in HepG2 cells cultured by the hanging drop method. Drug Metab Pharmacokinet, 2017. 32(5): p. 265–272. PubMed

Dash AK, et al., Heterodimerization of Retinoid X Receptor with Xenobiotic Receptor partners occurs in the cytoplasmic compartment: Mechanistic insights of events in living cells. Exp Cell Res, 2017. 360(2): p. 337–346. PubMed

van de Winkel A, et al., Expression, localization and polymorphisms of the nuclear receptor PXR in Barrett’s esophagus and esophageal adenocarcinoma. BMC Gastroenterol, 2011. 11: p. 108. PubMed PMC

Matic M, et al., A novel approach to investigate the subcellular distribution of nuclear receptors in vivo. Nucl Recept Signal, 2009. 7: p. e004. PubMed PMC

Saradhi M, et al., Pregnane and Xenobiotic Receptor (PXR/SXR) resides predominantly in the nuclear compartment of the interphase cell and associates with the condensed chromosomes during mitosis. Biochim Biophys Acta, 2005. 1746(2): p. 85–94. PubMed

Squires EJ, Sueyoshi T, and Negishi M, Cytoplasmic localization of pregnane X receptor and ligand-dependent nuclear translocation in mouse liver. J Biol Chem, 2004. 279(47): p. 49307–14. PubMed

Deuring JJ, et al., Pregnane X receptor activation constrains mucosal NF-κB activity in active inflammatory bowel disease. PLoS One, 2019. 14(10): p. e0221924. PubMed PMC

Xie W. and Tian Y, Xenobiotic receptor meets NF-kappaB, a collision in the small bowel. Cell Metab, 2006. 4(3): p. 177–8. PubMed

Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future

Mixture Effects of Tryptophan Intestinal Microbial Metabolites on Aryl Hydrocarbon Receptor Activity

Profiling Tryptophan Catabolites of Human Gut Microbiota and Acute-Phase Protein Levels in Neonatal Dried Blood Specimens