Tryptophan Metabolites as Mediators of Microbiota-Gut-Brain Communication: Focus on Isatin

Медведев, А. Е.; Buneeva, O. A.

doi:10.3389/fnbeh.2022.922274

Cited by 10 publications

(6 citation statements)

References 56 publications

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“…Trp is an essential amino acid supplied by dietary protein whose degradation occurs throughout the small intestine [ 27 , 28 ]. The gastrointestinal tract harbors numerous species with the capacity to synthesize indole and indole-containing compounds.…”

Section: The Tryptophan-indole Microbial Pathwaymentioning

confidence: 99%

Turning Microbial AhR Agonists into Therapeutic Agents via Drug Delivery Systems

et al. 2023

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Developing therapeutics for inflammatory diseases is challenging due to physiological mucosal barriers, systemic side effects, and the local microbiota. In the search for novel methods to overcome some of these problems, drug delivery systems that improve tissue-targeted drug delivery and modulate the microbiota are highly desirable. Microbial metabolites are known to regulate immune responses, an observation that has resulted in important conceptual advances in areas such as metabolite pharmacology and metabolite therapeutics. Indeed, the doctrine of “one molecule, one target, one disease” that has dominated the pharmaceutical industry in the 20th century is being replaced by developing therapeutics which simultaneously manipulate multiple targets through novel formulation approaches, including the multitarget-directed ligands. Thus, metabolites may not only represent biomarkers for disease development, but also, being causally linked to human diseases, an unexploited source of therapeutics. We have shown the successful exploitation of this approach: by deciphering how signaling molecules, such as the microbial metabolite, indole-3-aldehyde, and the repurposed drug anakinra, interact with the aryl hydrocarbon receptor may pave the way for novel therapeutics in inflammatory human diseases, for the realization of which drug delivery platforms are instrumental.

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Section: The Tryptophan-indole Microbial Pathwaymentioning

confidence: 99%

Turning Microbial AhR Agonists into Therapeutic Agents via Drug Delivery Systems

et al. 2023

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“…Notably, the fragment-screening hits include 3CL pro structures with two fragments based on the reversible, covalent binding motif isatin (indoline-2,3-dione). Isatin is both a known covalent inhibitor of cysteine proteases (Badavath et al, 2022;Cheke et al, 2022;Jiang & Hansen, 2011;Webber et al, 1996;Zhou et al, 2006) and an endogenous compound that is present at concentrations of 0.1-10 mM in human tissue (Medvedev et al, 2007) and the gut microbiome (Medvedev & Buneeva, 2022). 20 isatin derivatives have been reported by the COVID Moonshot consortium (Morris et al, 2021), with RapidFire assay IC 50 values as low as 740 nM [SMILES code Cc1nc(CN2C(=O)C(=O)c3cc(Br)ccc32)cs1; Moonshot submission No.…”

Section: Introductionmentioning

confidence: 99%

Fragment-based screening targeting an open form of the SARS-CoV-2 main protease binding pocket

Huang,

Metz,

Lange

et al. 2024

Acta Crystallogr D Struct Biol

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To identify starting points for therapeutics targeting SARS-CoV-2, the Paul Scherrer Institute and Idorsia decided to collaboratively perform an X-ray crystallographic fragment screen against its main protease. Fragment-based screening was carried out using crystals with a pronounced open conformation of the substrate-binding pocket. Of 631 soaked fragments, a total of 29 hits bound either in the active site (24 hits), a remote binding pocket (three hits) or at crystal-packing interfaces (two hits). Notably, two fragments with a pose that was sterically incompatible with a more occluded crystal form were identified. Two isatin-based electrophilic fragments bound covalently to the catalytic cysteine residue. The structures also revealed a surprisingly strong influence of the crystal form on the binding pose of three published fragments used as positive controls, with implications for fragment screening by crystallography.

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“…A wide range of biological activity of isatin is realized by numerous isatin-binding proteins localized in various intracellular compartments of the brain and peripheral tissues. According to the data of proteomic profiling of the brain, a number of proteins that bind to isatin play an important role in the development of neurodegenerative pathology [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Characteristics of behavioral reactions and the profile of brain isatin-binding proteins of rats with the rotenone-induced experimental parkinsonism

et al. 2023

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The neurotoxins rotenone and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (МPTP) are used for modeling Parkinson's disease in animals (PD). They induce the mitochondrial respiratory chain dysfunction, which leads to the dopaminergic (DA) neuron degeneration. The advantage of the rotenone model consists in ability of rotenone to cause neurodegeneration showing symptoms and molecular biological characteristics similar to those of PD. Isatin (indoldione-2,3) is an endogenous regulator found in tissues and biological fluids of humans and animals. It exhibits a broad range of biological activity mediated by numerous isatin-binding proteins. In this work we have investigated behavioral reactions and profiles of brain isatin-binding proteins of rats with Parkinson's syndrome (PS) in comparison with the corresponding parameters of MPTP-induced Parkinsonism in mice. Systemic injection of rotenone caused severe PS comparable with the effect of MPTP injection. It was accompanied by significant body weight loss, death, oligokinesia, muscular rigidity, and postural instability of animals. In spite of the same pathogenic basis of PS caused by rotenone and MPTP, the molecular mechanisms of their action differ. In the case of rotenone-induced PS, the pool of isatin-binding proteins common of the control rats and the rats with PS (146) significantly exceeded the pool of the common proteins of control mice and mice with PS induced by MPTP, whether right after neurotoxin injection (27), or (all the more) in a week after the MPTP injection (14). The comparison of isatin-binding proteins specific of the animals with MPTP-induced PS and with the rotenone-induced PS (as compared with the control animals) revealed total absence of proteins common of these two models of PD. It is to be noted that both neurotoxins particularly affected the proteins participating in the signal transmission and enzyme activity regulation. The changes of the profile of isatin-binding proteins in response to the injection of rotenone suggest that the neuroprotector isatin could also influence positively in the case of the rotenone model of PD.

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Tryptophan Metabolites as Mediators of Microbiota-Gut-Brain Communication: Focus on Isatin

Cited by 10 publications

References 56 publications

Turning Microbial AhR Agonists into Therapeutic Agents via Drug Delivery Systems

Turning Microbial AhR Agonists into Therapeutic Agents via Drug Delivery Systems

Fragment-based screening targeting an open form of the SARS-CoV-2 main protease binding pocket

Characteristics of behavioral reactions and the profile of brain isatin-binding proteins of rats with the rotenone-induced experimental parkinsonism

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