Article
Pharmacology & Pharmacy
Fanni Annamaria Boros, Laszlo Vecsei
Summary: Inhibition of TDO has the potential to alleviate motor and non-motor dysfunctions in PD, but concerns over harmful effects of long-term TDO inhibition exist. To fully exploit the possibilities of TDO inhibitory treatment, further research into developing selective TDO inhibitor compounds with good bioavailability and models replicating systemic origin PD symptoms is needed.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2021)
Article
Multidisciplinary Sciences
Simon Klaessens, Vincent Stroobant, Delia Hoffmann, Mads Gyrd-Hansen, Luc Pilotte, Nathalie Vigneron, Etienne De Plaen, Benoit J. Van den Eynde
Summary: The stability of tryptophan 2,3-dioxygenase (TDO) largely controls tryptophan homeostasis, with high tryptophan levels stabilizing TDO's active tetrameric conformation and low levels triggering TDO degradation. This allows for quick adaptation of tryptophan catabolism to prevent excess tryptophan while maintaining physiological levels, crucial for neurological and immune homeostasis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Pharmacology & Pharmacy
Ana Dolsak, Stanislav Gobec, Matej Sova
Summary: This review discusses the key step of tryptophan metabolism and the importance of relevant enzymes in pathological conditions. In recent years, many inhibitors targeting these enzymes have been developed, and these inhibitors have entered clinical trials.
PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Biochemistry & Molecular Biology
Xiao-han Liu, Xiao-yue Zhai
Summary: Tryptophan metabolism is associated with various biological processes such as nerve conduction, inflammation, and the immune response. Clinical studies have shown that it plays a crucial role in tumor progression by modulating the immunosuppressive microenvironment through multiple mechanisms.
Article
Fisheries
Yimu Luan, Yaocen Wang, Wentong Zhang, Xuyuan Duan, Peng Su, Qingwei Li, Yue Pang, Meng Gou
Summary: This study cloned and identified six TRP-KYN pathway-related genes from the lamprey. These genes were found to play a role in immunosuppression, inflammatory response, and tumor suppression. The key gene Lj-TDO was highly expressed in the oral gland. Real-time quantitative PCR showed significant upregulation of TRP-KYN pathway-related genes after multi-stimulation. RNA interference of Lj-IDO2 regulated the expression of inflammatory factors. This study provides valuable insights into the ancestral features and functions of the TRP-KYN pathway, as well as its involvement in the immune responses of jawless vertebrates.
FISH & SHELLFISH IMMUNOLOGY
(2023)
Article
Immunology
Minah Kim, Petr Tomek
Summary: Blocking tryptophan catabolism mediated by IDO1 and TDO shows promise for sensitising cancer patients to immune checkpoint blockade. Understanding the immune-regulatory function of tryptophan catabolism could lead to optimized therapeutic strategies. Tryptophan may act as a rheostat of kynurenine-mediated immunosuppression by competing for entry into immune T-cells.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Chemistry, Medicinal
Rahul Singh, Deepak B. Salunke
Summary: IDO1 enzyme catalyzes the initial step of kynurenine pathway and is implicated in immune modulation, antioxidation, and cancer progression. Overexpression of IDO1 plays a pivotal role in immune evasion and cancer development. Research and development of IDO1 inhibitors holds significant potential in immunotherapy and disease treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Simon Klaessens, Vincent Stroobant, Etienne De Plaen, Benoit J. van den Eynde
Summary: This study reviews the main mechanisms contributing to tryptophan homeostasis and discusses the physiopathology of disorders associated with their dysfunction. Tryptophan is catabolized along the kynurenine pathway by the enzymes IDO1 and TDO. Recent data suggest that the stability of TDO protein is regulated by tryptophan, allowing tight control of tryptophanemia. Deficiency in TDO or the hepatic aromatic transporter SLC16A10 can lead to severe hypertryptophanemia, affecting immune and neurological homeostasis.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Jaswir Basran, Elizabeth S. Booth, Laura P. Campbell, Sarah J. Thackray, Mehul H. Jesani, Jonathan Clayden, Peter C. E. Moody, Christopher G. Mowat, Hanna Kwon, Emma L. Raven
Summary: 【】The kynurenine pathway is the major route of tryptophan metabolism, catalyzed by heme-dependent dioxygenase enzymes. The crystal structure of a bacterial TDO in complex with L-kynurenine is presented in this paper, revealing a mechanism for the hydrolysis of NFK in the active site. Hydrogen bonding interactions and heme 7-propionate anchor the L-kynurenine molecule into the pocket.
JOURNAL OF INORGANIC BIOCHEMISTRY
(2021)
Article
Oncology
Qingqing Liu, Shixian Hua, Xinyi Wang, Feihong Chen, Shaohua Gou
Summary: The designed conjugates targeting irinotecan and TDO inhibitor units could enhance antitumor activity by inhibiting TDO enzyme expression, blocking kynurenine production, inducing HepG2 cancer cell apoptosis, activating T cells, and improving tumor immune microenvironment.
CANCER IMMUNOLOGY IMMUNOTHERAPY
(2021)
Article
Chemistry, Medicinal
Cui Huo, Zongyuan Luo, Xiangli Ning, Xin Kang, Qin Yan, Yuying Guo, Guobo Li, Zhouyu Wang, Yuzhi Li, Shan Qian
Summary: In this study, we investigated the inhibition of tryptophan-2,3-dioxygenase (TDO) and indoleamine-2, 3-dioxygenase 1 (IDO1) and designed and synthesized a series of nitro-aryl 1H-indazole derivatives. Among these derivatives, HT-28 and HT-30 demonstrated nanomolar potency and excellent selectivity against TDO, while HT-37 showed dual-target inhibitory activity against IDO1 and TDO. Furthermore, HT-28 exhibited significant tumoricidal effects on multiple tumor cell lines.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Cell Biology
Filip Jovanovic, Visnja Jovanovic, Nebojsa Nick Knezevic
Summary: The development of chronic pain involves complex interactions among the nervous, immune, and endocrine systems. Chronic pain, lasting for more than 3 months, is increasingly common in the US adult population. Pro-inflammatory cytokines contribute to chronic pain and affect the tryptophan metabolism and the hypothalamic-pituitary-adrenal axis. Glucocorticoids and metabolites of the kynurenine pathway may serve as biomarkers and potential therapeutic targets for chronic pain.
Article
Pharmacology & Pharmacy
Azubuike Peter Ebokaiwe, Doris Olachi Obasi, Rex Clovis C. Njoku, Sharon Osawe, Olasiende Olusanya, Winner O. Kalu
Summary: Quercetin ameliorates hepatic-renal dysfunction induced by cyclophosphamide by alleviating oxidative-inflammatory stress and regulating the activities of immunosuppressive enzymes.
Article
Pharmacology & Pharmacy
Sevda Shayesteh, Gilles J. Guillemin, Amir Rashidian, Hedyeh Faghir-Ghanesefat, Ali R. Mani, Seyed Mohammad Tavangar, Ahmad R. Dehpour
Summary: The kynurenine pathway is upregulated in liver disease and is associated with disease severity. In an experimental model of cirrhosis, inhibition of IDO with 1-MT improved cardiac dysfunction and reduced systemic inflammation. Chronic administration of 1-MT also attenuated hepatic inflammation, fibrosis, and ductular proliferation in rats with biliary cirrhosis.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Review
Oncology
Yu Yao, Heng Liang, Xin Fang, Shengnan Zhang, Zikang Xing, Lei Shi, Chunxiang Kuang, Barbara Seliger, Qing Yang
Summary: IDO1, a heme-containing enzyme, plays a crucial role in the kynurenine pathway of tryptophan metabolism, with implications in immunity and neuronal function. Despite potential applications in cancer and neurodegenerative diseases, cautionary notes from clinical trials indicate a need for better understanding of IDO1 inhibition mechanisms.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Arnaud Osi, Damien Mahaut, Nikolay Tumanov, Luca Fusaro, Johan Wouters, Benoit Champagne, Aurelien Chardon, Guillaume Berionni
Summary: This study reveals the rational design and remarkable reactivity of a geometrically constrained boron Lewis superacid. It demonstrates the formation of non-classical electron deficient B-H-B type of bonding and enables challenging chemical transformations through the taming of pyramidal Lewis acid electrophilicity.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Medicinal
Arina Kozlova, Leopold Thabault, Nicolas Dauguet, Marine Deskeuvre, Vincent Stroobant, Luc Pilotte, Maxime Liberelle, Benoit Van den Eynde, Raphael Frederick
Summary: This study explored the impact of selenium incorporation in TDO2 inhibitors, demonstrating that chalcogen isosteric replacements can modulate the properties of compounds without disturbing their on-target activity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Leopold Thabault, Chiara Brustenga, Perrine Savoyen, Megane Van Gysel, Johan Wouters, Pierre Sonveaux, Raphael Frederik, Maxime Liberelle
Summary: This article describes the funding and support received for this research.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Immunology
Anke Breine, Megane Van Gysel, Mathias Elsocht, Clemence Whiteway, Chantal Philippe, Theo Quinet, Adam Valcek, Johan Wouters, Steven Ballet, Charles Van der Henst
Summary: This article investigates the issue of carbapenem-resistant Acinetobacter baumannii bacteria and identifies a compound with inhibitory activity against these strains.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Chemistry, Organic
Arnaud Osi, Nikolay Tumanov, Johan Wouters, Aurelien Chardon, Guillaume Berionni
Summary: A new boratriptycene derivative with a selenium atom in the bridgehead position of the triptycene scaffold was synthesized, and its Lewis acidity was evaluated experimentally and computationally. The introduction of a selenium atom allows precise modification of the pyramidalization of the boron atom environment, affecting the Lewis acidity parameters of the triarylborane.
SYNTHESIS-STUTTGART
(2023)
Article
Chemistry, Organic
Laurie Bodart, Johan Wouters
Summary: This study presents useful descriptors for discriminating structures with selenium-containing chalcogen bonds. The most relevant parameters for identifying conventional chalcogen bonds are the C-Se angle and the distance between X and the C-Se-C plane, while for chalcogen...pi bonds, the relevant parameters are the C-Se angle and the angle between the C-Se bond and the normal to the aromatic ring plane.
SYNTHESIS-STUTTGART
(2023)
Article
Chemistry, Medicinal
Marie Haufroid, Alexander N. Volkov, Johan Wouters
Summary: Tuberculosis remains as a major cause of death caused by a treatable pathogen. The increasing resistance to common antibiotics necessitates the development of new drugs with new therapeutic targets. The enzyme MtSerB2, which allows immune evasion of Mycobacterium tuberculosis, is a potential target for drug design. This study presents a new approach based on virtual screening for selecting harmine-derived compounds to inhibit MtSerB2. The affinity of these compounds for MtSerB2 is characterized through screening methods, providing structural information and the development of pharmacophore models for more complex inhibitors. This research may lead to the development of antimycobacterial molecules targeting MtSerB2 and inhibiting the growth of the pathogen.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Arnaud Osi, Nikolay Tumanov, Luca Fusaro, Johan Wouters, Guillaume Berionni, Aurelien Chardon
Summary: Isolation and characterization of highly reactive intermediates are important for understanding chemical reactivity. The chemistry of borylated sulfate, triflimidate, and triflate anions were studied in order to synthesize unique analogs of protonated Bronsted superacids. Complexes formed by borylation with a 9-boratriptycene derived Lewis super acid and a weakly coordinated anion were characterized in solution and in the solid state, exhibiting unique structures and reactivities.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Inorganic & Nuclear
Arnaud Osi, Nicolas Niessen, Damien Mahaut, Benoit Champagne, Aurelien Chardon, Nikolay Tumanov, Johan Wouters, Guillaume Berionni
Summary: The association between pyridine and collidine with a pyramidal triarylborane belonging to the 9-boratriptycene family is explored using NMR spectroscopy and X-ray diffraction analysis. Despite the large size and steric hindrance, the boron Lewis superacid enables the formation of a stable Lewis adduct. X-ray diffraction analysis reveals an exceptional deformation of the collidine moiety, resulting in a small twist of the collidine ring into a boat-like conformation. Computational investigations suggest that steric repulsions decrease the Gibbs free energy of Lewis adduct formation.
ZEITSCHRIFT FUR ANORGANISCHE UND ALLGEMEINE CHEMIE
(2023)
Article
Chemistry, Multidisciplinary
Laurie Bodart, Jeanne Body, Nikolay Tumanov, Tom Leyssens, Johan Wouters
Summary: This study identifies and characterizes four new solid forms of pyrimethamine and sulfathiazole, including a cocrystal and solvated salt cocrystals. The desolvation of the salt cocrystals leads to the formation of stable mixtures. Additionally, both the pyrimethamine-sulfathiazole cocrystal and solvated salt cocrystal show an increase in drug solubility.
CRYSTAL GROWTH & DESIGN
(2023)
Article
Biology
Elise Pierson, Florian De Pol, Marianne Fillet, Johan Wouters
Summary: This study provides a structural, biophysical, and enzymological characterization of Mycobacterium tuberculosis phosphoserine phosphatase MtSerB2. The enzyme exists in dimeric, trimeric, and tetrameric forms with different activity levels and interconverts through a conformationally flexible monomeric state. This research lays the foundation for future allosteric drug discovery and understanding of the enzyme's multifunctional properties.
COMMUNICATIONS BIOLOGY
(2023)
Article
Crystallography
Johan Wouters, Luc Van Meervelt
Summary: This article describes an easily accessible experimental set-up for growing large single crystals of two common sweeteners found in supermarkets, erythritol and xylitol. The crystallization process of these compounds demonstrates the principles of crystallization by evaporation. Additionally, a simple calorimetric set-up is used to showcase the endothermic nature of the dissolution of the sweeteners by measuring the heat of dissolution. The choice of these sweeteners also allows for visualization of their three-dimensional structure, crystal packing, and powder diffractograms using freely available tools.
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS
(2022)
Article
Materials Science, Multidisciplinary
Jasper Deckers, Tom Cardeynaels, Sandra Doria, Nikolay Tumanov, Andrea Lapini, Anitha Ethirajan, Marcel Ameloot, Johan Wouters, Mariangela Di Donato, Benoit Champagne, Wouter Maes
Summary: In this study, a series of strongly absorbing, heavy-atom-free, distyryl-BODIPY donor-acceptor dyads operating within the phototherapeutic window were reported. The diphenylamine and carbazole donors led to strong fluorescence, while dimethylacridine, phenoxazine, and phenothiazine units afford a decent fluorescence combined with the efficient formation of singlet oxygen. The excited state dynamics responsible for the differences within the BODIPY series were elucidated through photophysical analysis and quantum-chemical calculations.
JOURNAL OF MATERIALS CHEMISTRY C
(2022)
Article
Chemistry, Multidisciplinary
Anurag Singh, Aaron Torres-Huerta, Tom Vanderlinden, Nathan Renier, Luis Martinez-Crespo, Nikolay Tumanov, Johan Wouters, Kristin Bartik, Ivan Jabin, Hennie Valkenier
Summary: This study demonstrates the anion binding and anion transport properties of a series of calix[6]arenes decorated with halogen bond or hydrogen bond donating groups on their small rim. The results show that the halogen bond donating iodotriazole groups enable highly selective transport of chloride and nitrate anions, without the transport of protons or hydroxide.
CHEMICAL COMMUNICATIONS
(2022)
Article
Crystallography
Manon Mirgaux, Tanguy Scaillet, Arina Kozlova, Nikolay Tumanov, Raphael Frederick, Laurie Bodart, Johan Wouters
Summary: Recently, interest has grown in substituting nitrogen atoms with selenium, sulfur, or oxygen atoms in the design of potential cancer inhibitors. Single-crystal X-ray diffraction analyses were used to determine the structures of derivatives of 5-(1H-indol-3-yl)-2,1,3-benzotriazole, leading to observations of different crystal packing and supramolecular features depending on the substitution. Computational methods were also employed to better understand the effects of substitution on the compounds' ability to form chalcogen bonds and their flexibility.
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS
(2022)