Targeting Aryl hydrocarbon receptor for next-generation immunotherapies: Selective modulators (SAhRMs) versus rapidly metabolized ligands (RMAhRLs)

Dolciami, Daniela; Ballarotto, Marco; Gargaro, Marco; Cara, Carlota Lopez; Fallarino, Francesca; Macchiarulo, Antonio

doi:10.1016/j.ejmech.2019.111842

Cited by 36 publications

(27 citation statements)

References 187 publications

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“…The number of individual compounds that bind to and modulate AhR-mediated responses and genes is continually increasing, and includes structurally diverse synthetic chemicals (e.g., pharmaceuticals), phytochemicals, microbial metabolites and endogenous biochemicals, some of which may be “cognate” AhR ligands [ 4 , 5 , 6 , 94 , 96 , 103 , 104 , 105 , 106 , 107 ]. Most but not all of these compounds bind the receptor, with much lower binding affinities than observed for TCDD.…”

Section: Classification Of Ahr Ligands—sahrms or Not?mentioning

confidence: 99%

“…Most but not all of these compounds bind the receptor, with much lower binding affinities than observed for TCDD. Some of these AhR ligands fit into the category of rapidly metabolized AhR ligands (RMAhRLs) [ 106 , 107 ]. This part of the review will examine and provide some examples of how different classes of AhR ligands are highly selective in terms of their agonist and antagonist activities, suggesting that they are SAhRMs.…”

Section: Classification Of Ahr Ligands—sahrms or Not?mentioning

confidence: 99%

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Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

Safe

Jin

Park

et al. 2020

IJMS

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The aryl hydrocarbon receptor (AhR) was first identified as the intracellular protein that bound and mediated the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and dioxin-like compounds (DLCs). Subsequent studies show that the AhR plays an important role in maintaining cellular homeostasis and in pathophysiology, and there is increasing evidence that the AhR is an important drug target. The AhR binds structurally diverse compounds, including pharmaceuticals, phytochemicals and endogenous biochemicals, some of which may serve as endogenous ligands. Classification of DLCs and non-DLCs based on their persistence (metabolism), toxicities, binding to wild-type/mutant AhR and structural similarities have been reported. This review provides data suggesting that ligands for the AhR are selective AhR modulators (SAhRMs) that exhibit tissue/cell-specific AhR agonist and antagonist activities, and that their functional diversity is similar to selective receptor modulators that target steroid hormone and other nuclear receptors.

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Section: Classification Of Ahr Ligands—sahrms or Not?mentioning

confidence: 99%

Section: Classification Of Ahr Ligands—sahrms or Not?mentioning

confidence: 99%

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

Safe

Jin

Park

et al. 2020

IJMS

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“…Beyond conventional agonists and antagonists, the new concept of selective AhR modulators (SAhRMs) designates any AhR ligand that lacks agonist activity but can repress the expression of acute inflammatory phase genes. These molecules are reviewed in [73].…”

Section: Ahrmentioning

confidence: 99%

Tryptophan Metabolism as a Pharmacological Target

Modoux

Rolhion

Mani

et al. 2021

Trends in Pharmacological Sciences

188

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L-Tryptophan is an essential amino acid required for protein synthesis. It undergoes an extensive and complex metabolism along several pathways, resulting in many bioactive molecules acting in various organs through different action mechanisms. Enzymes involved in its metabolism, metabolites themselves, or their receptors, represent potential therapeutic targets, which are the subject of dynamic research. Disruptions in L-tryptophan metabolism are reported in several neurological, metabolic, psychiatric, and intestinal disorders, paving the way to develop drugs to target it. This review will briefly describe L-tryptophan metabolism and present and discuss the most recent pharmacological developments targeting it. Highlights L-Tryptophan (L-Trp) is metabolized via three pathways: the indole pathway in bacteria and the kynurenine and serotonin pathways in mammalian cells. Disruptions in L-Trp metabolism are reported in several diseases making L-Trp metabolism a promising therapeutic target. Manipulating L-Trp metabolism is an attractive therapeutic strategy. Key enzymes of L-Trp metabolism are targets of inhibitors currently undergoing clinical trials in cancerology, dermatology, and gastroenterology. Serotonin and aryl hydrocarbon receptor (AhR) receptors are targeted in the treatment of gastrointestinal diseases, inflammation, and many cancers. Next-generation probiotics producing indoles are being developed for their ability to activate AhR in the gut.

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“…These compounds are quite abundant and persistent in the environment due to their long half-life and bioaccumulation in the trophic chain. Their toxicity has been largely documented in humans as well as in other species with estimates indicating that more than 90% of the human exposures occur via contaminated food (21,(35)(36)(37)(38)(39)(40)(41). However, over the last decades, a wide variety of agonists from multiple sources such as the environment, the microbiome, the diet and metabolism have been shown to activate AHR.…”

Section: Ahr Signalingmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor as a Modulator of Anti-viral Immunity

2021

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which interacts with a wide range of organic molecules of endogenous and exogenous origin, including environmental pollutants, tryptophan metabolites, and microbial metabolites. The activation of AHR by these agonists drives its translocation into the nucleus where it controls the expression of a large number of target genes that include the AHR repressor (AHRR), detoxifying monooxygenases (CYP1A1 and CYP1B1), and cytokines. Recent advances reveal that AHR signaling modulates aspects of the intrinsic, innate and adaptive immune response to diverse microorganisms. This review will focus on the increasing evidence supporting a role for AHR as a modulator of the host response to viral infection.

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Targeting Aryl hydrocarbon receptor for next-generation immunotherapies: Selective modulators (SAhRMs) versus rapidly metabolized ligands (RMAhRLs)

Cited by 36 publications

References 187 publications

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

Tryptophan Metabolism as a Pharmacological Target

The Aryl Hydrocarbon Receptor as a Modulator of Anti-viral Immunity

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