Synthesis and initial evaluation of radioactive 5-I-α-methyl-tryptophan: a Trp based agent targeting IDO-1.
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ABSTRACT:
SUBMITTER: Giglio BC
PROVIDER: S-EPMC6540958 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Indoleamine 2,3-dioxygenase (IDO1) plays a special role in the biology of various cancer types, because it breaks down the essential amino acid tryptophan for immune cell activation. Upregulation of IDO1 significantly correlates with the number of various T cell types in tumor tissues in melanoma and other cancers, suggesting that IDO expression is linked with effective and ineffective ('exhausted') immune response in cancer. Based on the reported IDO inhibitors (?-Methylated and indole-N-methylated tryptophan (Trp)), here we report the synthesis of potential IDO1 imaging agents through direct introduction of 18F into the tryptophan aromatic ring. Overall, the resulting PET agents could be obtained in high radiochemical purity (>97%) with labeling yield ranges from 4.2-14.9% decay corrected yield. Using Trp as the model compound, our results also demonstrate that 18F could be directly introduced to the Trp backbone at the 4, 5, 6, and 7 position. Moreover, our initial imaging study suggests that 5-[18F]F-L-?-methyl tryptophan (5-[18F]F-AMT) holds great potential for cancer imaging. The success of this approach will provide researchers easy access to a library of Trp/Trp-derivative based PET agents for biomedical research, including potential IDO1 targeted imaging.
| S-EPMC5436511 | biostudies-literature
Project description:Tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO) alters inflammation and favors T-cell tolerance in cancer, but the underlying molecular mechanisms remain poorly understood. The integrated stress response kinase GCN2, a sensor of uncharged tRNA that is activated by amino acid deprivation, is recognized as an important effector of the IDO pathway. However, in a mouse model of inflammatory carcinogenesis, ablation of Gcn2 did not promote resistance against tumor development like the absence of IDO does, implying the existence of additional cancer-relevant pathways that operate downstream of IDO. Addressing this gap in knowledge, we report that the IDO-mediated catabolism of tryptophan also inhibits the immunoregulatory kinases mTOR and PKC-?, along with the induction of autophagy. These effects were relieved specifically by tryptophan but also by the experimental agent 1-methyl-D-tryptophan (D-1MT, also known as NLG8189), the latter of which reversed the inhibitory signals generated by IDO with higher potency. Taken together, our results implicate mTOR and PKC-? in IDO-mediated immunosuppressive signaling, and they provide timely insights into the unique mechanism of action of D-1MT as compared with traditional biochemical inhibitors of IDO. These findings are important translationally, because they suggest broader clinical uses for D-1MT against cancers that overexpress any tryptophan catabolic enzyme (IDO, IDO2 or TDO). Moreover, they define mTOR and PKC-? as candidate pharmacodynamic markers for D-1MT responses in patients recruited to ongoing phase IB/II cancer trials, addressing a current clinical need.
| S-EPMC3525601 | biostudies-literature
Project description:Antibiotic resistance is a continually growing challenge in the treatment of various bacterial infections worldwide. New drugs and new drug targets are necessary to curb the threat of infectious diseases caused by multidrug-resistant pathogens. The tryptophan biosynthesis pathway is essential for bacterial growth but is absent in higher animals and humans. Drugs that can inhibit the bacterial biosynthesis of tryptophan offer a new class of antibiotics. In this work, we combined a structure-based strategy using in silico docking screening and molecular dynamics (MD) simulations to identify compounds targeting the α subunit of tryptophan synthase with experimental methods involving the whole-cell minimum inhibitory concentration (MIC) test, solution state NMR, and crystallography to confirm the inhibition of L-tryptophan biosynthesis. Screening 1,800 compounds from the National Cancer Institute Diversity Set I against α subunit revealed 28 compounds for experimental validation; four of the 28 hit compounds showed promising activity in MIC testing. We performed solution state NMR experiments to demonstrate that a one successful inhibitor, 3-amino-3-imino-2-phenyldiazenylpropanamide (Compound 1) binds to the α subunit. We also report a crystal structure of Salmonella enterica serotype Typhimurium tryptophan synthase in complex with Compound 1 which revealed a binding site at the αβ interface of the dimeric enzyme. MD simulations were carried out to examine two binding sites for the compound. Our results show that this small molecule inhibitor could be a promising lead for future drug development.
| S-EPMC8820114 | biostudies-literature
Project description:The catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is a key step in tolerance effected by a variety of cell types, including mesenchymal stromal cells (MSCs). Trp catabolism generates molecules known as kynurenines, whose tolerance mechanisms involve activation of the Aryl Hydrocarbon Receptor (AHR). A synthetic analog of Trp, 1-methyl tryptophan (1MT), is a selective inhibitor of IDO enzymatic activity being utilized in cancer immunotherapy trials. We hypothesized 1MT might activate AHR independently of its effects on IDO. We demonstrate MSCs express AHR protein, and that in vitro treatment with 1MT causes AHR nucleotranslocation. Upon analyzing mRNA, we observed transcriptional upregulation of cytochrome p450 1a1 and 1b1 by 1MT racemic mixture (R-MT), consistent with AHR-activation. RNA-sequencing identified Nrf2, MAPK12 and IL-1a as downstream targets of 1MT. We demonstrate 1a1 and 1b1 activation by 1MT in IDO+ MSC following interferon-γ (IFN-γ) activation, suggesting AHR signaling is uncoupled from IDO catalytic function. Such a mechanism of action for 1MT may extend its usage to a wider range of patients, irrespective of tumor IDO expression. These observations support a novel paradigm by which AHR-activating compounds like 1MT can be used in cancer immunotherapy to stimulate a pro-inflammatory response.
| S-EPMC5696151 | biostudies-literature
Project description:Nitration of N(alpha),N(1)-bis(trifluoroacetyl)-l-tryptophan methyl ester with HNO(3) in acetic anhydride at 0 degrees C provides N(alpha)-trifluoroacetyl-2-nitro-l-tryptophan methyl ester in 67% yield, whereas nitration in trifluoroacetic acid at 0 degrees C gives N(alpha)-trifluoroacetyl-6-nitro-l-tryptophan methyl ester in 69% yield.
| S-EPMC4335804 | biostudies-literature
Project description:Metabolism of the essential amino acid tryptophan is a key metabolic pathway that restricts antitumor immunity and is a drug development target for cancer immunotherapy. Tryptophan metabolism is active in brain tumors including gliomas and promotes a malignant phenotype and contributes to the immunosuppressive tumor microenvironment. In recent years, improved understanding of the regulation and downstream function of tryptophan metabolism has been significantly expanded beyond the initial in vitro observation that the enzyme indoleamine-2,3-dioxygenase 1 (IDO1) promotes the depletion of intracellular tryptophan. Here, we revisit the specific roles of tryptophan metabolites in regulating brain functioning and neuronal integrity as well as in the context of brain tumors. This review summarizes recent developments in identifying key regulators, as well as the cellular and molecular effects of tryptophan metabolism with a particular focus on potential therapeutic targets in glioma.
| S-EPMC8373719 | biostudies-literature
Project description:Nitrogen (N) and phosphorus (P) are the most limiting factors for plant growth. Some microorganisms improve the uptake and availability of N and P, minimizing chemical fertilizer dependence. It has been published that the RD64 strain, a Sinorhizobium meliloti 1021 strain engineered to overproduce indole-3-acetic acid (IAA), showed improved nitrogen fixation ability as compared to the wild type 1021 strain. We present here data showing that RD64 is also highly effective in mobilizing P from insoluble sources such as phosphate rock (PR). Under P-limiting conditions, the higher P-mobilizing activity of RD64, as compared to the 1021 wild type strain, is connected with the up-regulation of genes coding for the high-affinity P transport system, the induction of acid phosphatase activity and the increased secretion into the growth media of malic, succinic and fumaric acids. Medicago truncatula plants nodulated by RD64 (Mt-RD64), when grown under P-deficient conditions, released higher amounts of another P-solubilizing organic acid, the 2-hydroxyglutaric acid, as compared to the plants nodulated by the wild-type strain (Mt-1021). It has already been shown that Mt-RD64 plants exhibited a higher dry weight production as compared to Mt-1021 plants. Here we report that also P-starved Mt-RD64 plants show a significant increase both in shoot and root fresh weight when compared to P-starved Mt-1021 plants. We discuss how, in a rhizobium-legume model system, a balanced interplay of different factors linked to the bacterial IAA over-production rather than IAA production per se stimulates plant growth under stressful environmental conditions, and in particular, under P-starvation. Two-conditions experiment: untreated vs. Trp-treated cells. Biological replicates: 6 untreated control, 6 treated samples, independently grown and harvested. One replicate per array.
2010-05-20 | E-GEOD-21743 | biostudies-arrayexpress
Project description:Nitrogen (N) and phosphorus (P) are the most limiting factors for plant growth. Some microorganisms improve the uptake and availability of N and P, minimizing chemical fertilizer dependence. It has been published that the RD64 strain, a Sinorhizobium meliloti 1021 strain engineered to overproduce indole-3-acetic acid (IAA), showed improved nitrogen fixation ability as compared to the wild type 1021 strain. We present here data showing that RD64 is also highly effective in mobilizing P from insoluble sources such as phosphate rock (PR). Under P-limiting conditions, the higher P-mobilizing activity of RD64, as compared to the 1021 wild type strain, is connected with the up-regulation of genes coding for the high-affinity P transport system, the induction of acid phosphatase activity and the increased secretion into the growth media of malic, succinic and fumaric acids. Medicago truncatula plants nodulated by RD64 (Mt-RD64), when grown under P-deficient conditions, released higher amounts of another P-solubilizing organic acid, the 2-hydroxyglutaric acid, as compared to the plants nodulated by the wild-type strain (Mt-1021). It has already been shown that Mt-RD64 plants exhibited a higher dry weight production as compared to Mt-1021 plants. Here we report that also P-starved Mt-RD64 plants show a significant increase both in shoot and root fresh weight when compared to P-starved Mt-1021 plants. We discuss how, in a rhizobium-legume model system, a balanced interplay of different factors linked to the bacterial IAA over-production rather than IAA production per se stimulates plant growth under stressful environmental conditions, and in particular, under P-starvation.
2010-05-20 | GSE21743 | GEO
Project description:Immune escape is a fundamental trait of cancer in which the Th1-type cytokine interferon- γ (IFN-γ) seems to play a key role. Among other tumoricidal biochemical pathways, IFN-γ induces the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) in a variety of cells including macrophages, dendritic cells (DCs) and tumor cells. IDO activity has been shown to reflect the extent and the course in a plethora of malignancies including prostate, colorectal, pancreatic, cervical, endometrial, gastric, lung, bladder, ovarian, esophageal and renal cell carcinomas, glioblastomas, mesotheliomas, and melanomas. Furthermore IDO activity during malignant tumor diseases seems to be part of the tumoricidal immune defense strategy, which in the long run is detrimental to the host, when tryptophan deprivation and production of pro-apoptotic tryptophan catabolites counteract T-cell responsiveness.
| S-EPMC3195236 | biostudies-literature
Project description:Transient receptor potential (TRP) channels are a group of membrane proteins involved in the transduction of a plethora of chemical and physical stimuli. These channels modulate ion entry, mediating a variety of neural signaling processes implicated in the sensation of temperature, pressure, and pH, as well as smell, taste, vision, and pain perception. Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory disorders. In the pursuit of new treatments for these disorders, it was discovered that cannabinoids can modulate a certain subset of TRP channels. The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were all found to contain channels that can be modulated by several endogenous, phytogenic, and synthetic cannabinoids. To date, six TRP channels from the three subfamilies mentioned above have been reported to mediate cannabinoid activity: TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8. The increasing data regarding cannabinoid interactions with these receptors has prompted some researchers to consider these TRP channels to be "ionotropic cannabinoid receptors." Although CB1 and CB2 are considered to be the canonical cannabinoid receptors, there is significant overlap between cannabinoids and ligands of TRP receptors. The first endogenous agonist of TRPV1 to be discovered was the endocannabinoid, anandamide (AEA). Similarly, N-arachidonyl dopamine (NADA) and AEA were the first endogenous TRPM8 antagonists discovered. Additionally, Δ9-tetrahydrocannabinol (Δ9-THC), the most abundant psychotropic compound in cannabis, acts most potently at TRPV2, moderately modulates TRPV3, TRPV4, TRPA1, and TRPM8, though Δ9-THC is not reported to modulate TRPV1. Moreover, TRP receptors may modulate effects of synthetic cannabinoids used in research. One common research tool is WIN55,212-2, a CB1 agonist that also exerts analgesic effects by desensitizing TRPA1 and TRPV1. In this review article, we aim to provide an overview and classification of the cannabinoid ligands that have been reported to modulate TRP channels and their therapeutic potential.
| S-EPMC6340993 | biostudies-literature