Article
Chemistry, Medicinal
Xiong Fang, Qian Meng, Huijun Zhang, Xiao Fang, Lina S. Huang, Xingquan Zhang, Robert T. Schooley, Aaron Ciechanover, Jing An, Yan Xu, Ziwei Huang
Summary: This study successfully designed and synthesized a new and potent small molecule CXCR4 antagonist, named HF51116. HF51116 exhibited very high CXCR4 binding affinity and inhibited SDF-1α-induced cell migration, calcium mobilization, and CXCR4 internalization. It also demonstrated inhibitory effects on HIV-1 infection via CXCR4. Analysis of the interaction between HF51116 and CXCR4 suggested that the compound recognizes the minor and major subpockets of CXCR4 and blocks G protein-dependent downstream signal pathways. HF51116 may serve as a prototype for developing CXCR4-targeted therapeutics.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Libao Liu, Jordi Doijen, Thomas D'huys, Yenthel Verhaegen, Wim Dehaen, Steven De Jonghe, Dominique Schols, Tom Van Loy
Summary: Our study on CCR8 ligands in in vitro cell-based assays revealed differences in signaling pathways and cell migration induced by different ligands. Human CCL1 most efficiently induced cell migration and required Gll-γ signaling, while other CCR8 ligands did not depend on Gll-γ signaling for cell migration. Despite all tested CCR8 agonists being full agonists for calcium mobilization, significant contributions of Gll-γ signaling were only observed in human and viral CCL1.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
S. Jeson Sangaralingham, Kanupriya Whig, Satyamaheshwar Peddibhotla, R. Jason Kirby, Hampton E. Sessions, Patrick R. Maloney, Paul M. Hershberger, Heather Mose-Yates, Becky L. Hood, Stefan Vasile, Shuchong Pan, Ye Zheng, Siobhan Malany, John C. Burnett
Summary: The discovery and development of an oral, small molecule GC-A PAM holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases by enhancing ANP-mediated cGMP generation and inhibiting cardiomyocyte hypertrophy.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Neurosciences
Alasdair J. Gibb
Summary: NMDA receptors, specifically the triheteromeric structure of GluN1/GluN2B/GluN2D receptors, play fundamental roles in synaptic physiology and have implications for pharmacological research. This study reviews the mechanism of action of drugs targeting allosteric antagonists at these receptors.
Article
Biochemistry & Molecular Biology
Willem F. J. Karstens, Wiro M. B. P. Menge, Gijs Martens, Sanne J. N. Op Het Veld, Jacobus Th. H. van Eupen, Marco Demon, Tanja A. E. van Achterberg, Monica J. Arisse-Thijssen, Ellen W. H. Santegoeds-Lenssen, Miranda M. C. van der Lee, Ruud Ubink, Roel J. Arends, Aloys Sesink, Marion Blomenrohr, C. Marco Timmers
Summary: This paper describes the discovery of a novel small molecule TSH-R antagonist, SYD5115 (67), with nanomolar potency. SYD5115 also blocks the synthesis of thyroid hormone T4 induced by stimulating antibodies after a single oral dose. During optimization, issues such as low metabolic stability and potential mutagenicity of the initial compounds had to be addressed.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Chao Wang, Bidong Zhang, Arne Kruger, Xiaochen Du, Lidia Visser, Alexander S. S. Domling, Carsten Wrenger, Matthew R. Groves
Summary: This study describes a series of small-molecule inhibitors targeting P. falciparum ATC with low nanomolar binding affinities, selectively binding to a previously unreported allosteric pocket, inhibiting ATC activation.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Xinqian Wang, Dingqiang Lu, Dandan Peng, Danyang Liu, Yujiao Liu, Yixuan Liu, Wei Xu, Yifei Zhang, Chenyu Xu, Ruijuan Ren, Ming Li, Jinghan Gao, Guangchang Pang
Summary: This study constructed a nanogold receptor sensor using hCCR3 as the molecular recognition element and horseradish peroxidase as the signal amplifier, aiming to quantitatively evaluate the interaction between chemokines and hCCR3. The results indicated that chemokines interact with hCCR3 at low concentrations, and reversible hCCR3 inhibitors solely inhibit hCCR3, not CCLs.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Chemistry, Multidisciplinary
Qing-lin Wu, Li-yuan Cui, Wen-yu Ma, Sha-sha Wang, Zhao Zhang, Zhong-ping Feng, Hong-shuo Sun, Shi-feng Chu, Wen-bin He, Nai-hong Chen
Summary: This study characterized the therapeutic potential of a novel CCR5 antagonist A14 in treating ischemic stroke mice. A14 dose-dependently inhibited the CCR5 activity and exerted protective effects against neuronal ischemic injury in vitro and in vivo. Compared to maraviroc, A14 had better BBB permeability and showed sustained protective effects against motor impairment.
ACTA PHARMACOLOGICA SINICA
(2023)
Review
Pharmacology & Pharmacy
Alexander Domling, Xin Li
Summary: In 2020, the anti-TNF monoclonal antibody Humira generated a huge cumulative sales, surpassing Lipitor as the most successful drug in the industry. However, due to limitations in CNS applications, small-molecule drugs are being developed to benefit a wider range of diseases.
DRUG DISCOVERY TODAY
(2022)
Review
Pharmacology & Pharmacy
Jiaqi Yao, Yiran Tao, Zelin Hu, Junjie Li, Ziyi Xue, Ya Zhang, Yi Lei
Summary: This paper provides a comprehensive review of ER's structural functions and highlights the recent advancements in novel drugs targeting ER, namely SERD and SERCA, focusing on their structural optimization strategies and future directions. It also discusses the therapeutic potential and challenges of these drugs in breast cancer and other ER-related diseases.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Immunology
Kimia Ghasemi, Kosar Ghasemi
Summary: Chemokines and their receptors play crucial roles in immune responses. CXCR4, a GPCR, interacts with SDF-1 to regulate multiple signaling pathways and has potential therapeutic value in cancer treatment. MSX-122, an orally available CXCR4 antagonist, shows promising anti-cancer properties, especially in treating metastatic cancers.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Alexander O. Shpakov
Summary: Allosteric regulation plays a critical role in the functioning of GPCRs and their signaling pathways. The complexity of allosteric effects caused by various regulators determines the multiplicity and topology of allosteric sites in GPCRs. These sites are involved in the regulation of receptor activity, GPCR-complex formation, and endocytosis. They are also targets for synthetic allosteric regulators and modulators. The review provides an overview of the principles and mechanisms of GPCRs allosteric regulation, the diversity of allosteric sites, and the endogenous and synthetic allosteric regulators.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Daniela G. Dengler, Kaleeckal G. Harikumar, Sirkku Pollari, Qing Sun, Brock T. Brown, Aki Shinoki-Iwaya, Robert Ardecky, Laurence J. Miller, Eduard A. Sergienko
Summary: This study identified three structurally related scaffolds that positively modulate SCTR, providing insights into their activity, cooperativity, and specificity. The structural optimization resulted in analog B2, which enhances signaling of secretin peptides and prolongs their residence time. These scaffolds may serve as novel pharmacologic tools to elucidate SCTR-and GLP-1R-specific signaling pathways.
BIOCHEMICAL PHARMACOLOGY
(2021)
Review
Endocrinology & Metabolism
Anh T. N. Nguyen, Quan L. Tran, Jo-Anne Baltos, Samantha M. McNeill, Diep T. N. Nguyen, Lauren T. May
Summary: G protein-coupled receptors (GPCRs) are targeted by approximately one-third of FDA-approved small molecule drugs. Among the four adenosine GPCR subtypes, the adenosine A(1) receptor (A(1)R) plays important physiological roles in humans. A(1)R has been identified as a potential therapeutic target for various conditions, but the development of small molecule drugs targeting A(1)R has been limited by unwanted effects. An alternative approach using A(1)R allosteric modulators that target a different binding site shows promise in overcoming these limitations. This review provides insights into the therapeutic potential of A(1)R and recent advances in understanding its allosteric modulation.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Review
Oncology
Sean Kraus, Thomas Kolman, Austin Yeung, Dustin Deming
Summary: Chemokine receptor antagonists show promise in cancer treatment by influencing cell infiltration into the tumor microenvironment. Targeting different chemokine receptors is a promising strategy for improving treatment responses in cancer patients. Additional research in this area has the potential to dramatically enhance patient outcomes.
CURRENT ONCOLOGY REPORTS
(2021)
Article
Pharmacology & Pharmacy
Maria Buur Nordskov Gabe, Liv von Voss, Jenna Elizabeth Hunt, Sarina Gadgaard, Laerke Smidt Gasbjerg, Jens Juul Holst, Hannelouise Kissow, Bolette Hartmann, Mette Marie Rosenkilde
Summary: Biased GLP-2R agonists with modifications at the N-terminal have shown improved therapeutic effects on gut and bone growth. Variants like [F6A], [F6W], and [S7W] have less GLP-2R internalization and enhanced gut trophic actions, including increased small intestine weight, villus height, and crypt depth.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Endocrinology & Metabolism
Morten S. Hansen, Kent Soe, Line L. Christensen, Paula Fernandez-Guerra, Nina W. Hansen, Rachael A. Wyatt, Claire Martin, Rowan S. Hardy, Thomas L. Andersen, Jacob B. Olesen, Bolette Hartmann, Mette M. Rosenkilde, Moustapha Kassem, Alexander Rauch, Caroline M. Gorvin, Morten Frost
Summary: Drugs targeting the GIP receptor have potential as treatments for type-2 diabetes and obesity. GIP can directly act on human bone cells to inhibit bone resorption, increase bone formation, and improve osteoblast survival. Therefore, these drugs may reduce bone resorption while preserving bone formation.
EUROPEAN JOURNAL OF ENDOCRINOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Maja L. Nybo, Jone M. Kvam, John E. Nielsen, Hanne Frederiksen, Katja Spiess, Kristian H. R. Jensen, Sarina Gadgaard, Anna L. S. Walser, Jesper S. Thomsen, Pamela Cowin, Anders Juul, Martin B. Jensen, Mette M. Rosenkilde
Summary: A mouse model lacking the adhesion receptor ADGRA3 (GPR125) exhibited infertility despite having normal spermatogenesis and epididymal sperm count. This infertility was caused by a post-pubertal hormonal imbalance and fluid retention, leading to the blockage between the ejaculatory duct and the urethra, resembling the etiologies of obstructive azoospermia in human male infertility.
Article
Medicine, Research & Experimental
Sarina Gadgaard, Johanne A. Windelov, Sine P. Schiellerup, Jens J. Holst, Bolette Hartmann, Mette M. Rosenkilde
Summary: In this study, lipidated GLP-2R agonists were created and tested for their effects on the intestine and bone. The variants with lipidations at positions 12, 16, and 20 showed improved potency and efficacy compared to native GLP-2.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Biochemistry & Molecular Biology
Viktoria M. S. Kjaer, Viktorija Daugvilaite, Tomasz M. Stepniewski, Christian M. Madsen, Astrid S. Jorgensen, Kaustubh R. Bhuskute, Asuka Inoue, Trond Ulven, Tau Benned-Jensen, Siv A. Hjorth, Gertrud M. Hjorto, Ee Von Moo, Jana Selent, Mette M. Rosenkilde
Summary: The chemotactic receptor GPR183 and its ligand 7 alpha,25-OHC play important roles in immune cell positioning. The internalization of GPR183 is influenced by the C terminus, β-arrestin, caveolin, and dynamin. β-arrestin enhances ligand-induced internalization of GPR183, but it is not required. Internalization and chemotaxis are regulated by distinct mechanisms involving G protein activation and β-arrestin-mediated desensitization. These findings have implications for the development of GPR183-targeting drugs for specific diseases.
Editorial Material
Pharmacology & Pharmacy
Mette Marie Rosenkilde, Jesper Mosolff Mathiesen
Summary: G-protein-coupled receptors (GPCRs) are important drug targets with diverse ligands and coupling partners. Laboute et al.'s recent work identified GPR158 as a metabotropic glycine receptor (mGlyR), revealing a novel neuromodulatory system with implications for cognition and affective states.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Francisco Conceicao, Daniela M. Sousa, Sofia Tojal, Catarina Lourenco, Carina Carvalho-Maia, Helena Estevao-Pereira, Joao Lobo, Marina Couto, Mette M. Rosenkilde, Carmen Jeronimo, Meriem Lamghari
Summary: Sympathetic nervous system and β2-adrenergic receptor are implicated in breast cancer, particularly bone metastasis. Epinephrine levels are elevated in breast cancer patients. Activation of β2-adrenergic receptor inhibits osteoclast differentiation and resorption activity in non-metastatic breast cancer, but not in metastatic bone tropic breast cancer.
Article
Pharmacology & Pharmacy
Felix Faas, Amalie Norskov, Peter J. Holst, Anne-Marie Andersson, Katrine Qvortrup, Signe Mathiasen, Mette M. Rosenkilde
Summary: This study successfully translated Ga-12/13 signaling to Ga(q) signaling output by engineering Ga-q chimeras, providing a new approach for studying the function of aGPCRs, drug screening, and deorphanization.
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2023)
Review
Endocrinology & Metabolism
Laerke S. Gasbjerg, Mette M. M. Rosenkilde, Juris J. J. Meier, Jens J. J. Holst, Filip K. K. Knop
Summary: Tirzepatide is a unimolecular co-agonist of GLP-1 and GIP receptors approved for treating type 2 diabetes. The contribution of GIP receptor activation to the clinical effects of tirzepatide is uncertain. Based on current knowledge, tirzepatide may not have a classical co-activating mode of action, and we propose three hypotheses for its mode of action.
DIABETES OBESITY & METABOLISM
(2023)
Article
Microbiology
Gary Ewart, Michael M. Bobardt, Bo Hjorth Bentzen, Yannan Yan, Audrey Thomson, Klaus Klumpp, Stephen Becker, Mette Rosenkilde, Michelle Miller, Philippe Gallay
Summary: The small molecule drug BIT225 inhibits the ion channel activity of the Coronavirus envelope (E) protein, preventing weight loss and death in SARS-CoV-2 infected mice. The drug shows broad-spectrum antiviral activity and significantly reduces viral load and inflammation markers. These findings support the clinical evaluation of BIT225 for the treatment of human SARS-CoV-2 infection.
Article
Chemistry, Medicinal
Jon Vabeno, Marta Oliva-Santiago, Astrid S. Jorgensen, Stefanie Karlshoj, Mette M. Rosenkilde
Summary: Research has shown that residue positions 3.32 and 7.39 play a critical role in signal transduction of CXCR1, but have less effect on CXCR2. These positions form a salt bridge between TM helices 3 and 7, which is important for CXCR1 function.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Masa Mavri, Sanja Glisic, Milan Sencanski, Milka Vrecl, Mette M. Rosenkilde, Katja Spiess, Valentina Kubale
Summary: This study found that all BILF1 receptors undergo dynamin-dependent, clathrin-mediated constitutive endocytosis. In addition, recycling and degradation pathways were proposed for BILF1 receptors after internalization. These findings provide a foundation for further exploration of the translational potential of PLHV BILFs and offer new insights into receptor trafficking.
CELLULAR & MOLECULAR BIOLOGY LETTERS
(2023)
Article
Multidisciplinary Sciences
Andreas Lindqvist, Mia Abels, Liliya Shcherbina, Mtakai Ngara, Dmytro Kryvokhyzha, Sabrina Chriett, Matteo Riva, Abul Fajul, Mohammad Barghouth, Cheng Luan, Lena Eliasson, Olav Larsen, Mette M. Rosenkilde, Enming Zhang, Erik Renstrom, Nils Wierup
Summary: CART is expressed in pancreatic islet cells and neuronal elements, and has insulinotropic effects. We identified GPR162 as the receptor that mediates the effects of CART in pancreatic beta cells. Silencing GPR162 reduced the binding of CART to the receptor and attenuated CART-induced exocytosis and insulin secretion. Furthermore, CART was found to regulate cytoskeletal arrangement through GPR162.
Article
Biochemistry & Molecular Biology
Olav Larsen, Sara Schuermans, Anna Walser, Stavroula Louka, Ida Aaberg Lillethorup, Jon Vabeno, Katrine Qvortrup, Paul Proost, Mette M. Rosenkilde
Summary: This study investigates the signaling capacity of peptides related to inflammatory chemokines. The peptides showed weak potency but retained their signaling on CCR1, while none of the peptides generated a signal on CCR5. However, a tetrapeptide derived from CCL3 acted as a positive modulator on CCR5.
Article
Chemistry, Multidisciplinary
Viktoria Madeline Skovgaard Kjaer, Tomasz Maciej Stepniewski, Brian Medel-Lacruz, Lisa Reinmuth, Marija Ciba, Elisabeth Rexen Ulven, Massimiliano Bonomi, Jana Selent, Mette Marie Rosenkilde
Summary: The G protein-coupled receptor GPR183 uses two ligand entry channels to recognize chemically diverse ligands. The study reveals the ligand binding pathway of GPR183 and its importance in understanding the receptor's functionality and ligand recognition.