Review
Pharmacology & Pharmacy
Kazuhide Inoue, Makoto Tsuda
Summary: Chronic pain, especially neuropathic pain, is a significant clinical issue due to the ineffectiveness of available drugs. Research on extracellular ATP and P2 receptors in pain signaling provides insight into the mechanisms underlying chronic pain and potential therapeutic targets.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Milica Gusic, Klaus Benndorf, Christian Sattler
Summary: Our study reveals that each occupied binding site contributes to channel activation in P2X7 receptors. While the occupation of a single binding site can activate the channels, three bound ligands maximally stabilize the open state, suggesting a stepwise activation process for P2X7 receptors.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Pharmacology & Pharmacy
Jasmin Ballout, Rebecca Classen, Katrin Richter, Veronika Grau, Martin Diener
Summary: This study found that ionotropic P2X receptors are involved in the regulation of intestinal ion transport in rat colonic epithelia.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Review
Pharmacology & Pharmacy
Fritz Markwardt
Summary: Patch clamp investigations help understand the molecular function of single ion channels. The human P2X7 receptor is an ATP-gated ion channel involved in inflammatory and nociceptive reactions. Specific residues and domains play crucial roles in ion channel function.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Nicoleta Sandu, Claudia G. Chilom, Melinda David, Monica Florescu
Summary: This study investigated the interaction between the hydrophilic drug levothyroxine (LT4) and bovine serum albumin (BSA). Various techniques including UV-vis measurements, Fourier-transform infrared spectroscopy (FT-IR), fluorescence, fluorescence resonance energy transfer (FRET), Surface Plasmon Resonance (SPR), and molecular docking analysis were used. The results showed that LT4 binds to BSA through ground-state complex formation, driven mainly by hydrogen bonds and van der Waals forces. The immobilization of BSA was found to be crucial for the binding of LT4. These findings have important implications for understanding the pharmacological significance of LT4-protein binding.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Biochemistry & Molecular Biology
Qun-qi Hu, Xiao-fen He, Yi-qi Ma, Li-qian Ma, Si-ying Qu, Han-zhi Wang, Yu-rong Kang, Lu-hang Chen, Xiang Li, Bo-yu Liu, Xiao-mei Shao, Jun-fan Fang, Yi Liang, Jian-qiao Fang, Yong-liang Jiang
Summary: The study indicates the significant role of P2X4 and P2X7 in DNP, and the analgesic effect of electroacupuncture in reducing thermal hyperalgesia and the expression of P2X4 and P2X7.
PURINERGIC SIGNALLING
(2023)
Article
Neurosciences
Meng-Xi Xu, Guo-Li Zhao, Xin Hu, Han Zhou, Shu-Ying Li, Fang Li, Yanying Miao, Bo Lei, Zhongfeng Wang
Summary: Microglia play a role in the inflammatory response and retinal ganglion cell damage in glaucoma. This study examined the mechanisms of microglial proliferation and migration in a mouse model of chronic ocular hypertension. The results showed that the P2X7 receptor (P2X7R) was involved in microglial proliferation, while the P2X4 receptor (P2X4R) was involved in microglial migration. The interaction between Muller cells and microglia was found to be important in regulating microglial proliferation and migration in glaucoma development.
NEUROSCIENCE BULLETIN
(2022)
Article
Neurosciences
Cinzia Volonte, Susanna Amadio
Summary: This review focuses on the impact of inter-cellular signaling mediated by extracellular nucleosides and nucleotides on pathophysiological processes in the nervous system. Purine and pyrimidine molecules are prevalent chemical messengers in the animal and plant kingdoms. The authors emphasize the importance of considering a comprehensive purinergic network perspective, particularly in pathological conditions. They present updated research on P2X7 and P2X4 receptors, which are extensively studied in amyotrophic lateral sclerosis, and highlight the significance of understanding their actions.
Article
Biology
Anna Durner, Ellis Durner, Annette Nicke
Summary: The large intracellular C-terminus of the pro-inflammatory P2X7 ion channel receptor (P2X7R) is associated with diverse functions. Cryo-EM structures recently revealed the presence of a membrane-associated anchoring domain, an open-state stabilizing cap domain, and a globular ballast domain with unknown functions. By incorporating an environment-sensitive fluorescent amino acid into P2X7Rs and performing voltage clamp fluorometry, researchers found that the ballast domain functions independently from the extracellular ATP binding domain and may require additional ligands or protein interactions.
Article
Biochemistry & Molecular Biology
Sin-Lih Tan, Muruj Barri, Peace Atakpa-Adaji, Colin W. Taylor, Ewan St John Smith, Ruth D. Murrell-Lagnado
Summary: It was found that lysosomal P2X4 receptors are activated downstream of plasma membrane P2X7 and H-1 histamine receptor stimulation. The activation of P2X4 receptors results in an increase in near-lysosome cytosolic [Ca2+] and triggers changes in lysosome properties, including enlargement and redistribution within the cell. The findings suggest that lysosomal P2X4 receptors play a role in regulating lysosomal Ca2+ release and membrane trafficking.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Tanveer A. A. Wani, Ahmed H. H. Bakheit, Seema Zargar, Nojood Altwaijry, Mashooq Ahmad Bhat, Hamad M. M. Alkahtani, Lamees S. S. Al-Rasheed
Summary: The presence of the p-aryl/cyclohexyl ring in the N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazine carbothioamide derivative (2C) enhances its antifungal properties. This study investigates the interaction of 2C with BSA using spectroscopic methods and molecular docking. The results demonstrate a strong binding interaction between BSA and 2C through hydrogen and van der Waals forces, with binding constants ranging from 2.91 x 10(5) to 1.29 x 10(5).
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Valerie J. Brock, Insa M. A. Wolf, Marco Er-Lukowiak, Niels Lory, Tobias Staehler, Lena-Marie Woelk, Hans-Willi Mittrucker, Christa E. Mueller, Friedrich Koch-Nolte, Bjoern Rissiek, Rene Werner, Andreas H. Guse, Bjoern-Philipp Diercks
Summary: The purinergic cation channels P2X4 and P2X7 play a role in the formation of initial Ca2+ microdomains in T cells within a short time after activation. Their activation is crucial for T cell activation.
Article
Neurosciences
Yuan Chang-Halabi, Jose Cordero, Xander Sarabia, Daniela Villalobos, Nelson P. Barrera
Summary: This review discusses the mechanism of interaction between P2X and 5-HT3 receptors, providing current evidence supporting this crosstalk at the structural to the transduction pathway level. We expect this work to guide the design of further experiments to obtain a comprehensive view of the neuropharmacological role of these interacting receptors.
Article
Plant Sciences
Nina Gloeckner, Sven zur Oven-Krockhaus, Leander Rohr, Frank Wackenhut, Moritz Burmeister, Friederike Wanke, Eleonore Holzwart, Alfred J. Meixner, Sebastian Wolf, Klaus Harter
Summary: Protein-protein interaction studies are crucial for understanding cellular signaling. This study used three-fluorophore FRET and FRET-fluorescence lifetime imaging microscopy techniques to demonstrate the formation of a ternary complex involving Receptor-Like Protein 44, Brassinosteroid Insensitive 1, and Brassinosteroid Insensitive 1 Associated Kinase 1 in living plant cells. The researchers also found that this complex is localized in a distinct plasma membrane nanodomain.
Article
Immunology
Andrew Young, Ariel Isaacs, Connor A. P. Scott, Naphak Modhiran, Christopher L. D. McMillan, Stacey T. M. Cheung, Jennifer Barr, Glenn Marsh, Nazia Thakur, Dalan Bailey, Kenneth S. M. Li, Hayes K. H. Luk, Kin-Hang Kok, Susanna K. P. Lau, Patrick C. Y. Woo, Wakako Furuyama, Andrea Marzi, Paul R. Young, Keith J. Chappell, Daniel Watterson
Summary: The COVID-19 pandemic has demonstrated the importance of vaccine platform technologies in combating emerging infectious diseases. In this study, the molecular clamp, a subunit vaccine platform technology, was used to develop vaccines for four different viruses. The results showed that the vaccines were stable and induced a neutralizing immune response. Animal studies also demonstrated that the vaccines provided protection against viral challenge.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Pedro Valada, Sonja Hinz, Christin Vielmuth, Catia R. Lopes, Rodrigo A. Cunha, Christa E. Mueller, Joao Pedro Lopes
Summary: Inosine has neuroprotective effects by indirectly modifying the activity of adenosine receptors and controlling synaptic transmission and plasticity. It acts as a ligand of adenosine receptors with low affinity and shows higher affinity towards the rat A(3) receptor. The impact of inosine on synaptic transmission and plasticity is mediated by modification of extracellular levels of adenosine through equilibrative nucleoside transporters.
PURINERGIC SIGNALLING
(2023)
Article
Chemistry, Medicinal
Andhika B. B. Mahardhika, Anastasiia Ressemann, Sarah E. E. Kremers, Mariana S. Gregorio S. Castanheira, Clara T. T. Schoeder, Christa E. E. Mueller, Thanigaimalai Pillaiyar
Summary: The study synthesized a series of DIM derivatives and evaluated their affinities and efficacies for human CB receptor subtypes. The compound di-(4-cyano-1H-indol-3-yl)methane showed the highest potency as a CB2 receptor agonist and has potential as a novel drug for inflammatory diseases.
ARCHIV DER PHARMAZIE
(2023)
Article
Pharmacology & Pharmacy
Jan H. Voss, Haneen Al-Hroub, Robin Gedschold, Jennifer M. Dietrich, Evelyn Gaffal, Marieta Toma, Stefan Kehraus, Gabriele M. Koenig, Peter Brust, Bernd K. Fleischmann, Daniela Wenzel, Winnie Deuther-Conrad, Christa E. Mueller
Summary: G protein is identified as a potential drug target for treating complex diseases. The development of specific radiotracers allows for disease diagnosis and research.
Article
Biochemistry & Molecular Biology
Chunyang Bi, Laura Schaekel, Salahuddin Mirza, Katharina Sylvester, Julie Pelletier, Sang -Yong Lee, Thanigaimalai Pillaiyar, Jean Sevigny, Christa E. Mueller
Summary: Ticlopidine is an antithrombotic prodrug that inhibits platelet function by covalently blocking the P2Y12 receptor on thrombocytes. It was found that Ticlopidine also inhibits CD39, an enzyme involved in ATP hydrolysis. In this study, a comprehensive analysis of Ticlopidine derivatives was conducted, leading to the discovery of benzotetrahydropyridines as a novel class of allosteric CD39 inhibitors.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Malgorzata Frankowska, Karolina Wydra, Agata Suder, Magdalena Zaniewska, Dawid Gawlinski, Joanna Miszkiel, Anna Furgala-Wojas, Kinga Salat, Malgorzata Filip, Christa E. Mueller, Katarzyna Kiec-Kononowicz, Magdalena Kotanska
Summary: This study discovered three novel selective ligands for GPR18, including one agonist and two antagonists. The activation of GPR18 has similar effects to the CB receptor system, impacting emotional behavior, food intake, and pain activity. Therefore, GPR18 represents a potential therapeutic target for mood, pain, and/or eating disorders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Editorial Material
Chemistry, Medicinal
Jeffrey Aube, Craig W. Lindsley, Christa E. Mueller
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Mariam Tahoun, Marianne Engeser, Luca Svolacchia, Paul Martin Sander, Christa E. E. Mueller
Summary: This study investigates the stability and degradation of the oxygen-complexing prosthetic group of hemoglobin, heme, under various conditions expected to occur during fossilization. The results reveal that heme is most stable under anaerobic reductive conditions and least stable in the presence of H2O2. The presence of oxygen and H2O2 leads to the cleavage of heme and the formation of hematinic acid. The role of iron cation in heme degradation is confirmed, as heme lacking iron remains more stable. This study provides valuable insights into the fate of heme during fossilization.
Editorial Material
Chemistry, Medicinal
Jeffrey Aube, Craig W. Lindsley, Christa E. Mueller
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Multidisciplinary Sciences
Jan H. Voss, Max Cruesemann, Christian R. O. Bartling, Stefan Kehraus, Asuka Inoue, Gabriele M. Koenig, Kristian Stromgaard, Christa E. Mueller
Summary: This study investigated the inhibitory effects of macrocyclic depsipeptides YM-254890 and FR900359 on Gaq/11 proteins and observed significant differences in dissociation kinetics between these compounds and their hydrogenated, tritium-labeled derivatives. Results showed that small structural modifications had a major impact on the residence time of the macrocyclic depsipeptides. FR exhibited pseudo-irreversible binding, while YM had a faster dissociation rate. The isopropyl anchor in FR and some derivatives was found to be essential for slow dissociation. These findings provide a basis for future drug design strategies to modulate residence times of macrocyclic Gq protein inhibitors, which play a crucial role in therapeutic outcomes.
Article
Chemistry, Multidisciplinary
Tobias Claff, Jonathan G. Schlegel, Jan H. Voss, Victoria J. Vaassen, Renato H. Weisse, Robert K. Y. Cheng, Sandra Markovic-Mueller, Denis Bucher, Norbert Straeter, Christa E. Mueller
Summary: The authors report the crystal structures of A(2A)AR in complex with Etrumadenant, revealing a previously unknown interaction. These findings have implications for the design of selective receptor antagonists.
COMMUNICATIONS CHEMISTRY
(2023)
Editorial Material
Chemistry, Medicinal
Jeffrey Aube, Craig W. Lindsley, Christa E. Mueller
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Michal Zaluski, Tadeusz Karcz, Anna Drabczynska, Christin Vielmuth, Agnieszka Olejarz-Maciej, Monika Gluch-Lutwin, Barbara Mordyl, Agata Siwek, Grzegorz Satala, Christa E. Muller, Katarzyna Kiec-Kononowicz
Summary: Multitarget drugs designed with a hybrid dopamine-xanthine core have potential as drug candidates for neurodegenerative diseases. Further development of monoamine oxidase B (MAO-B) inhibitors with A(2A) adenosine receptor (A(2A)AR) antagonistic properties led to additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D-2 receptor (D2R) agonistic activity. The compounds showed MAO-B inhibition combined with A(2A)AR affinity, and some compounds exhibited enhanced PDE-inhibitory and D2R-agonistic activity through structural modifications. The multitarget drugs also demonstrated antioxidant properties in vitro and neuroprotective effects in a cellular model.
Article
Biochemistry & Molecular Biology
Nina Geiger, Viktoria Diesendorf, Valeria Roll, Eva-Maria Koenig, Helena Obernolte, Katherina Sewald, Julian Breidenbach, Thanigaimalai Pillaiyar, Michael Guetschow, Christa E. Mueller, Jochen Bodem
Summary: Recently, we investigated novel pyridyl indole esters and peptidomimetics as potent inhibitors of SARS-CoV-2 main protease. We analyzed the impact of these compounds on viral replication and found that their effectiveness varied in different cell lines. In Huh-7 cells, the protease inhibitors suppressed viral replication by up to 5 orders of magnitude, while in Calu-3 cells, suppression by 2 orders of magnitude was achieved. Three pyridin-3-yl indole-carboxylates showed antiviral activity in all cell lines and also in human precision-cut lung slices.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Daniel Marx, Mohamed Wessam Alnouri, Sophie Clemens, Robin Gedschold, Yvonne Riedel, Ghazl Al Hamwi, Thanigaimalai Pillaiyar, Jorg Hockemeyer, Vigneshwaran Namasivayam, Christa E. Mueller
Summary: This study discovered a xanthine derivative that activates the main variant of MRGPRX4, and optimization resulted in analogs with high potency and metabolic stability. These compounds are promising tool compounds for exploring the potential of MRGPRX4 as a future drug target.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Meeting Abstract
Immunology
R. Winzer, E. Schneider, A. Rissiek, I. Ricklefs, S. Brenna, B. Rissiek, C. E. Mueller, E. Tolosa
EUROPEAN JOURNAL OF IMMUNOLOGY
(2022)