Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

Coletti, Alice; Greco, Francesco; Dolciami, Daniela; Camaioni, Emidio; Sardella, Roccaldo; Pallotta, Maria Teresa; Volpi, Claudia; Orabona, Ciriana; Grohmann, Ursula; Macchiarulo, Antonio

doi:10.1039/c7md00109f

Cited by 32 publications

(21 citation statements)

References 85 publications

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“…Crystallographic studies and site-directed mutagenesis experiments of IDO1 have shed light on the overall architecture, key residues, and structural features of small-molecule-binding pockets of the enzyme (Fig. 5A), as reviewed elsewhere (52). These studies unveiled that IDO1 folds into a globular structure comprising a small noncatalytic domain and a large catalytic domain.…”

Section: Nas Confers Immunosuppressive Effects On Dcs Via Increased Cmentioning

confidence: 91%

Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation

Mondanelli

Coletti

Greco

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite N-acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.

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Section: Nas Confers Immunosuppressive Effects On Dcs Via Increased Cmentioning

confidence: 91%

Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation

Mondanelli

Coletti

Greco

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…[12][13][14] In this framework, academic groups and pharmaceutical companies have been engaged in developing IDO1 inhibitors with optimal pharmacological properties to be advanced in clinical trials. [15] These efforts have yielded potent and selective competitive and non-competitive inhibitors that bind to the catalytic site of IDO1, with or without direct interactions with different redox states of the heme cofactor. [16][17][18][19][20] More recently, potent inhibitors that specifically interact with a heme-free form of IDO1 have also been reported, supporting the notion that the enzyme exists in a complex equilibrium between an apo state and a catalytically competent heme-bound state.…”

Section: Introductionmentioning

confidence: 99%

Tracking Hidden Binding Pockets Along the Molecular Recognition Path of l‐Trp to Indoleamine 2,3‐Dioxygenase 1

et al. 2019

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Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the oxidative cleavage of l-Tryptophan (l-Trp) to yield N-formyl-kynurenine in the first and rate limiting step of the kynurenine pathway. Bioactive metabolites, involved in the regulation of important immunological responses and neurological processes, are then produced by downstream enzymes along the pathway. Inhibitors of IDO1 are being designed and developed as therapeutic agents for immuno-oncology. In this work, we investigated the molecular recognition path of l-Trp to IDO1, integrating biophysical methods with supervised molecular dynamics (suMD) and mutagenesis experiments. Results allowed disclosing for the first time high and low dissociation constants of l-Trp to IDO1, and the presence of a metastable interaction site located at the upper part of a channel whose borders are defined by the EF-loop and the C-terminal part of the JK-loop. Collectively, our results provide new clues for the design of next-generation IDO1 ligands.[a] Dr. interaction energy was calculated using NAMD Energy extension available in VMD. [55] The latter was used to render images and prepare movies of trajectories (ModelA.mpg, ModelB.mpg, Mod-elC.mpg; supporting information). 4 5 6 7 8

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“…Ongoing preclinical and clinical studies with different cancer models suggest that IDO1 assists cancer progression and metastasis . Studies also demonstrated the role of IDO1 in maintaining the maternal immune tolerance under normal physiological conditions ,. All these findings demonstrate the role of IDO1 enzyme in several diseases associated with immunosuppression.…”

Section: Introductionmentioning

confidence: 57%

“…1‐Methyl‐D‐tryptophan (D‐1MT, indoximod), N ‐hydroxyamidine INCB024360 (epacadostat), imidazole GDC‐0919 (navoximod), PF‐0684003 (EOS‐200271), BMS‐986205 (ONO‐7701) are the only five small‐molecule based IDO1 inhibitors that are now under clinical trials either alone or in combination with other antibodies . A wide range of heterocyclic moieties have emerged as excellent IDO1 inhibitors in our on‐going drug discovery programme.…”

Section: Introductionmentioning

confidence: 99%

Effect of Molecular Crowding Agents on the Activity and Stability of Immunosuppressive Enzyme Indoleamine 2,3‐Dioxygenase 1

2018

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Indoleamine 2,3-dioxygenase 1 (IDO1) plays pivotal role in regulating the metabolism of L-tryptophan (L-Trp) through kynurenine pathway, which is a well-established therapeutic target for the treatment of diseases associated with immunosuppression. Disproportionate expression of the enzyme and poor prediction of various types of malignancies make the development and clinical trials of IDO1 inhibitors extremely relevant. However, IDO1-based drug development has been hindered due to the use of idealized dilute buffer solution media during the screening and optimization of inhibitors, which do not reflect the highly crowded intracellular environment. In this report, IDO1 enzyme activity and its inhibitory activity against few potent compounds of N'-hydroxyamidine and aryl-substituted pyran scaffolds were investigated under macromolecularly crowded environment. The synthetic crowding agents were used to generate a cellular mimetic condition where IDO1 enzyme was found to retain its activity. A nonlinear relationship between the size and volume of the crowding agent with enzyme kinetic parameters was observed. The results suggest that judicious use of size and volume of the crowding agent could provide cellular mimetic environment. A very similar catalytic efficiency, inhibitory activity along with preservation of secondary structural content of IDO1 enzyme under the selected crowded media makes these crowding agents appropriate for further therapeutic application.

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Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

Abstract: Structure–function relationships of IDO1 and structure–activity relationships of inhibitors are discussed with an outlook on next generation IDO1 ligand.

Cited by 32 publications

References 85 publications

Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation

Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation

Tracking Hidden Binding Pockets Along the Molecular Recognition Path of l‐Trp to Indoleamine 2,3‐Dioxygenase 1

Effect of Molecular Crowding Agents on the Activity and Stability of Immunosuppressive Enzyme Indoleamine 2,3‐Dioxygenase 1

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