Xenobiotic receptors, such as the pregnane X receptor, regulate multiple host physiologic pathways including xenobiotic metabolism, certain aspects of cellular metabolism, and innate immunity. These ligand-dependent nuclear factors regulate gene expression via genomic recognition of specific promoters and transcriptional activation of the gene. Natural or endogenous ligands are not commonly associated with this class of receptors; however, since these receptors are expressed in a cell-type specific manner in the liver and intestines, there has been significant recent effort to characterize microbially derived metabolites as ligands for these receptors. In general, these metabolites are thought to be weak micromolar affinity ligands. This journal anniversary minireview focuses on recent efforts to derive potentially nontoxic microbial metabolite chemical mimics that could one day be developed as drugs combating xenobiotic receptor-modifying pathophysiology. The review will include our perspective on the field and recommend certain directions for future research. SIGNIFICANCE STATEMENT: Xenobiotic receptors (XRs) regulate host drug metabolism, cellular metabolism, and immunity. Their presence in host intestines allows them to function not only as xenosensors but also as a response to the complex metabolic environment present in the intestines. Specifically, this review focuses on describing microbial metabolite-XR interactions and the translation of these findings toward discovery of novel chemical mimics as potential drugs of the future for diseases such as inflammatory bowel disease.

• MeSH
• ligandy MeSH
• steroidní receptory * metabolismus   MeSH
• střeva MeSH
• transportní proteiny MeSH
• xenobiotika metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH

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.

• MeSH
• adenokarcinom MeSH
• antiflogistika chemie   farmakologie   MeSH
• hepatocyty MeSH
• indoly chemie   farmakologie   MeSH
• játra MeSH
• konformace proteinů MeSH
• lidé středního věku MeSH
• lidé MeSH
• molekulární mimikry MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory tračníku MeSH
• pregnanový X receptor chemie   metabolismus   MeSH
• racionální návrh léčiv MeSH
• střeva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Significant attrition limits drug discovery. The available chemical entities present with drug-like features contribute to this limitation. Using specific examples of promiscuous receptor-ligand interactions, a case is made for expanding the chemical space for drug-like molecules. These ligand-receptor interactions are poor candidates for the drug discovery process. However, provided herein are specific examples of ligand-receptor or transcription-factor interactions, namely, the pregnane X receptor (PXR) and the aryl hydrocarbon receptor (AhR), and itsinteractions with microbial metabolites. Discrete examples of microbial metabolite mimicry are shown to yield more potent and non-toxic therapeutic leads for pathophysiological conditions regulated by PXR and AhR. These examples underscore the opinion that microbial metabolite mimicry of promiscuous ligand-receptor interactions is warranted, and will likely expand the existing chemical space of drugs.

• MeSH
• léčivé přípravky * MeSH
• lidé MeSH
• objevování léků MeSH
• pregnanový X receptor * MeSH
• receptory aromatických uhlovodíků * MeSH
• steroidní receptory * MeSH
• střeva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH

For decades, traditional drug discovery has used natural product and synthetic chemistry approaches to generate libraries of compounds, with some ending as promising drug candidates. A complementary approach has been to adopt the concept of biomimicry of natural products and metabolites so as to improve multiple drug-like features of the parent molecule. In this effort, promiscuous and weak interactions between ligands and receptors are often ignored in a drug discovery process. In this Emerging Concepts article, we highlight microbial metabolite mimicry, whereby parent metabolites have weak interactions with their receptors that then have led to discrete examples of more potent and effective drug-like molecules. We show specific examples of parent-metabolite mimics with potent effects in vitro and in vivo. Furthermore, we show examples of emerging microbial ligand-receptor interactions and provide a context in which these ligands could be improved as potential drugs. A balanced conceptual advance is provided in which we also acknowledge potential pitfalls-hyperstimulation of finely balanced receptor-ligand interactions could also be detrimental. However, with balance, we provide examples of where this emerging concept needs to be tested. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry is a novel way to expand on the chemical repertoire of future drugs. The emerging concept is now explained using specific examples of the discovery of therapeutic leads from microbial metabolites.

• MeSH
• Bacteria chemie   MeSH
• biologické přípravky chemie   MeSH
• indoly chemie   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární mimikry MeSH
• objevování léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

The concept of small-molecule mimicry even of weak microbial metabolites present in rodents and humans, as a means to expand drug repertoires, is new. Hitherto, there are few proof-of-concept papers demonstrating utility of this concept. More recently, papers demonstrating mimicry of intestinal microbial metabolites could expand the drug repertoire for diseases such as inflammatory bowel disease (IBD). We opine that, as more functional metabolite-receptor pairings are discovered, small-molecule metabolite mimicry could be a significant effort in drug discovery.

• MeSH
• lidé MeSH
• mikrobiota * MeSH
• molekulární mimikry * MeSH
• objevování léků * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Mono-methylindoles (MMI) were described as agonists and/or antagonists of the human aryl hydrocarbon receptor (AhR). Here, we investigated the effects of MMI on AhR-CYP1A pathway in human hepatocytes and HepaRG cells derived from human progenitor hepatic cells. All MMI, except of 2-methylindole, strongly induced CYP1A1 and CYP1A2 mRNAs in HepaRG cells. Induction of CYP1A genes was absent in AhR-knock-out HepaRG cells. Consistently, CYP1A1 and CYP1A2 mRNAs and proteins were induced by all MMIs (except 2-methylindole), in human hepatocytes. The enzyme activity of CYP1A1 was inhibited by MMIs in human hepatocytes and LS180 colon cancer cells in a concentration-dependent manner (IC50 values from 1.2 μM to 23.8 μM and from 3.4 μM to 11.4 μM, respectively). Inhibition of CYP1A1 activity by MMI in human liver microsomes was much weaker as compared to that in intact cells. Incubation of parental MMI with human hepatocytes either diminished (4-methylindole, 6-methylindole) or enhanced (7-methylindole) their agonist effects on AhR in AZ-AHR reporter cells. In conclusion, overall effects of MMI on AhR-CYP1A pathway in human cells comprise the induction of CYP1A genes through AhR, the inhibition of CYP1A catalytic activity and possibly the metabolic transformation causing loss or gain of AhR agonist activity of parental compounds.

• MeSH
• cytochrom P-450 CYP1A1 antagonisté a inhibitory   biosyntéza   genetika   MeSH
• enzymová indukce MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• indoly farmakologie   MeSH
• induktory cytochromu P450 farmakologie   MeSH
• inhibitory cytochromu P450 farmakologie   MeSH
• jaterní mikrozomy účinky léků   enzymologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádorové buněčné linie MeSH
• nádory tračníku enzymologie   MeSH
• receptory aromatických uhlovodíků agonisté   genetika   metabolismus   MeSH
• senioři MeSH
• transkripční faktory bHLH agonisté   genetika   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Activation of human pregnane X receptor (hPXR) has been associated with induction of chemoresistance. It has been proposed that such chemoresistance via cytochrome P450/drug transporters can be reversed with the use of antagonists that specifically abrogate agonist-mediated hPXR activation. Unfortunately, proposed antagonists lack the specificity and appropriate pharmacological characteristics that allow these features to be active in the clinic. We propose that, ideally, an hPXR antagonist would be a cancer drug itself that is part of a "cancer drug cocktail" and effective as an hPXR antagonist at therapeutic concentrations. Belinostat (BEL), a histone deacetylase inhibitor approved for the treatment of relapsed/refractory peripheral T-cell lymphoma, and often used in combination with chemotherapy, is an attractive candidate based on its hPXR ligand-like features. We sought to determine whether these features of BEL might allow it to behave as an antagonist in combination chemotherapy regimens that include hPXR activators. BEL represses agonist-activated hPXR target gene expression at its therapeutic concentrations in human primary hepatocytes and LS174T human colon cancer cells. BEL repressed rifampicin-induced gene expression of CYP3A4 and multidrug resistance protein 1, as well as their respective protein activities. BEL decreased rifampicin-induced resistance to SN-38, the active metabolite of irinotecan, in LS174T cells. This finding indicates that BEL could suppress hPXR agonist-induced chemoresistance. BEL attenuated the agonist-induced steroid receptor coactivator-1 interaction with hPXR, and, together with molecular docking studies, the study suggests that BEL directly interacts with multiple sites on hPXR. Taken together, our results suggest that BEL, at its clinically relevant therapeutic concentration, can antagonize hPXR agonist-induced gene expression and chemoresistance.

• MeSH
• cytochrom P-450 CYP3A metabolismus   MeSH
• dospělí MeSH
• exprese genu účinky léků   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• irinotekan farmakologie   MeSH
• kyseliny hydroxamové farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádorové buněčné linie MeSH
• P-glykoproteiny metabolismus   MeSH
• pregnanový X receptor metabolismus   MeSH
• rifampin farmakologie   MeSH
• simulace molekulového dockingu metody   MeSH
• steroidní receptory metabolismus   MeSH
• sulfonamidy farmakologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH