Article
Biochemistry & Molecular Biology
Alexandra-Madelaine Tichy, Wang Lok So, Elliot J. Gerrard, Harald Janovjak
Summary: GPCRs are the largest human receptor family involved in various physiological processes. Researchers have optimized light-activated OptoXRs using structure-guided methods to improve signal coupling.
Review
Biochemistry & Molecular Biology
Andreas Bock, Marcel Bermudez
Summary: Bias agonism in GPCRs is likely a result of preferential allosteric coupling from the ligand binding pocket to a specific transducer, leading to selective activation of desired signaling pathways and potentially reducing side effects.
Article
Multidisciplinary Sciences
Li-Hua Zhao, Jingyu Lin, Su-Yu Ji, X. Edward Zhou, Chunyou Mao, Dan-Dan Shen, Xinheng He, Peng Xiao, Jinpeng Sun, Karsten Melcher, Yan Zhang, Xiao Yu, H. Eric Xu
Summary: This study presents the structures of CRF2R bound to UCN1 and coupled to G proteins G(11) and G(o), and compares them with the structure of CRF2R bound to G(s), uncovering the structural differences that determine the selective coupling of G protein subtypes by CRF2R.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Melissa Girard, Steve Dagenais Bellefeuille, Emilie Eiselt, Guillaume Arguin, Jean-Michel Longpre, Philippe Sarret, Fernand-Pierre Gendron
Summary: This study found that endosomal trafficking plays an important role in G protein-coupled receptor (GPCR) signaling. UDP selectively activates GPCR P2Y6 as a signaling molecule. The study found that MRS2693 and UDP have different effects on the internalization of the P2Y6 receptor, with MRS2693 inducing P2Y6 internalization through an independent caveolin-dependent mechanism. This study provides insights for the development of bias ligands that can influence P2Y6 signaling.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Mingcheng Qian, Zhengyang Sun, Xin Chen, Serge Van Calenbergh
Summary: This review provides an overview of the design strategy of bivalent ligands for G protein-coupled receptors (GPCRs) and mainly focuses on their application in studying and detecting GPCR dimerization in vitro and in vivo. Bivalent ligands have specific properties and are capable of binding to GPCR homodimers or heterodimers simultaneously, showing specific signal transduction compared to monovalent ligands.
BIOORGANIC CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Malarvizhi Gurusamy, Denise Tischner, Jingchen Shao, Stephan Klatt, Sven Zukunft, Remy Bonnavion, Stefan Guenther, Kai Siebenbrodt, Roxane-Isabelle Kestner, Tanja Kuhlmann, Ingrid Fleming, Stefan Offermanns, Nina Wettschureck
Summary: The G-protein-coupled receptor P2Y10, expressed in CD4 T cells, mediates RhoA activation and migration in response to lysophosphatidylserine and ATP, which are induced in T cells upon chemokine stimulation through an autocrine/paracrine loop.
NATURE COMMUNICATIONS
(2021)
Article
Biochemical Research Methods
K. Harini, S. Jayashree, Vikas Tiwari, Sneha Vishwanath, Ramanathan Sowdhamini
Summary: Computational docking can be used to predict specific allosteric binders for GPCRs, potentially reducing side effects associated with their nonspecific drug binding.
BIOINFORMATICS AND BIOLOGY INSIGHTS
(2021)
Review
Endocrinology & Metabolism
Fanhua Wang, Mingyao Liu, Ning Wang, Jian Luo
Summary: This review discusses the role of G-protein coupled receptors (GPCRs) in osteoarthritis (OA), including the pathophysiological processes involved, preclinical and clinical trial data, and the challenges in developing therapies targeting GPCRs for OA.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Emanuela Ruggiero, Irene Zanin, Marianna Terreri, Sara N. Richter
Summary: G-quadruplexes (G4s) play a crucial role in regulating key cellular processes, especially in cancer and virology. The use of selective G4 ligands helps understand the complexity of G4-mediated mechanisms in the viral life cycle, presenting a promising emerging antiviral approach.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Stefanie Kampen, Duc Duy Vo, Xiaoqun Zhang, Nicolas Panel, Yunting Yang, Mariama Jaiteh, Pierre Matricon, Per Svenningsson, Jose Brea, Maria Isabel Loza, Jan Kihlberg, Jens Carlsson
Summary: This study presents a structure-based strategy to design compounds with dual-target properties, which can both antagonize the A(2A) adenosine receptor and activate the D-2 dopamine receptor, showing promising potential as anti-parkinson drugs.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Medicinal
Rina Kwag, Jieon Lee, Doyoung Kim, Haeun Lee, Miyoung Yeom, Jiwan Woo, Yakdol Cho, Hak Joong Kim, Jeongjin Kim, Gyochang Keum, Byungsun Jeon, Hyunah Choo
Summary: By designing and synthesizing a series of compounds and evaluating their activities and selectivities, it was found that one compound showed good binding affinity and selectivity for 5-HT7R, exhibiting a G protein-biased antagonistic effect. The compound demonstrated inhibitory effects on self-grooming behavior in transgenic mice, indicating that 5-HT7R may be a potential therapeutic target for treating stereotypical behaviors in autism spectrum disorder.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biology
Ramon Cierco Jimenez, Nil Casajuana-Martin, Adrian Garcia-Recio, Lidia Alcantara, Leonardo Pardo, Mercedes Campillo, Angel Gonzalez
Summary: The study analyzed 119,069 natural variants in human olfactory receptors, revealing a significant diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a considerable number of changes occurring at the structurally conserved regions. Mutations in positions linked to the conserved GPCR activation mechanism were highlighted, which could imply phenotypic variation in olfactory perception.
Review
Chemistry, Medicinal
Mohammed Akli Ayoub, Ranjit Vijayan
Summary: Hemorphins, short peptides derived from hemoglobin's beta subunit, have diverse physiological effects, particularly in the nervous and renin-angiotensin systems. They modulate a variety of proteins, including enzymes and receptors, and target G protein-coupled receptors (GPCRs) pharmacologically and functionally. The implication of GPCRs in hemorphins' effects aids in understanding their molecular basis and suggests the hemorphin-GPCR axis as a potential therapeutic target in various systems.
Article
Chemistry, Medicinal
Amit Mahindra, Laura Jenkins, Sara Marsango, Mark Huggett, Margaret Huggett, Lindsay Robinson, Jonathan Gillespie, Muralikrishnan Rajamanickam, Angus Morrison, Stuart McElroy, Irina G. Tikhonova, Graeme Milligan, Andrew G. Jamieson
Summary: GPR84 is an inflammatory receptor associated with various diseases, and new high-quality antagonists are needed to study its pathophysiological role and validate it as a therapeutic target. Researchers have discovered a promising antagonist, compound 42, which could be further developed as a drug.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Amit Mahindra, Laura Jenkins, Sara Marsango, Mark Huggett, Margaret Huggett, Lindsay Robinson, Jonathan Gillespie, Muralikrishnan Rajamanickam, Angus Morrison, Stuart McElroy, Irina G. Tikhonova, Graeme Milligan, Andrew G. Jamieson
Summary: Researchers have discovered a novel GPR84 antagonist, compound 42, with favorable pharmacokinetic profile for further drug development. This compound can be used to investigate the pathophysiological role of GPR84 and validate it as a therapeutic target.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Plant Sciences
Thomas N. G. Handley, Hyon-Xhi Tan, Malcolm T. Rutledge, Hans Henning Brewitz, Joel D. A. Tyndall, Torsten Kleffmann, Margi I. Butler, Russell T. M. Poulter, Sigurd M. Wilbanks
NEW ZEALAND JOURNAL OF BOTANY
(2020)
Article
Medicine, Legal
F. Mueller, C. Bogdal, B. Pfeiffer, L. Andrello, A. Ceschi, A. Thomas, E. Grata
Summary: The paper discusses the first three deaths in Europe involving isotonitazene consumption, highlighting the acute intoxication caused by this potent opioid. The study found that isotonitazene concentration levels are very low but pose a real hazard for human health, based on autopsy findings and toxicological analysis.
FORENSIC SCIENCE INTERNATIONAL
(2021)
Article
Chemistry, Medicinal
Zohaib Rana, Joel D. A. Tyndall, Muhammad Hanif, Christian G. Hartinger, Rhonda J. Rosengren
Summary: Jazz90 and Jazz167 act as cytostatic HDAC inhibitors in AR-null prostate cancer cells by inhibiting cell growth with selective cytotoxicity, reducing HDAC activity, and increasing acetylation levels in cells. However, their apoptotic effects on PC3 and DU145 cells are limited, showing only a maximum of 7% cell population undergoing apoptosis after treatment with the compounds.
Review
Oncology
Veera V. Shivaji R. Edupuganti, Joel D. A. Tyndall, Allan B. Gamble
Summary: This review summarizes the significance of self-immolative linkers in prodrugs and ADCs in cancer treatment based on recent patent literature. Various triggerable self-immolative linkers are used to improve the efficacy and safety of targeting cancer cells. Site-specific activation of non-toxic prodrugs and ADCs can enhance selectivity for killing cancer cells.
RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY
(2021)
Article
Chemistry, Medicinal
Phuc N. H. Trinh, Daniel J. W. Chong, Katie Leach, Stephen J. Hill, Joel D. A. Tyndall, Lauren T. May, Andrea J. Vernall, Karen J. Gregory
Summary: This study presents the development of the first bifunctional ligands for adenosine A(1) receptor and adenosine A(3) receptor, which possess nanomolar affinity and irreversible binding properties. These ligands can aid in target validation and direct visualization of receptors in different native environments. They also exhibit moderate selectivity over A(2A) and A(2B) adenosine receptors.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Jimin Hwang, Natalie Strange, Rami Mazraani, Matthew J. Phillips, Allan B. Gamble, Wilhelmina M. Huston, Joel D. A. Tyndall
Summary: A new series of CtHtrA inhibitors were developed by proline ring expansion and Cg-substitutions, which showed significantly improved antichlamydial activity in vitro.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Jimin Hwang, Sonya Mros, Allan B. Gamble, Joel D. A. Tyndall, Arlene McDowell
Summary: Nanoparticle drug delivery systems offer a promising approach to address limitations of antimicrobial drugs. Controlled engineering of nanoparticle size using microfluidic technology can significantly improve drug delivery optimization.
Article
Microbiology
Yasmeen N. Ruma, Mikhail V. Keniya, Joel D. A. Tyndall, Brian C. Monk
Summary: The study characterized the wild type C. parapsilosis CYP51 and its resistance-causing point mutation Y132F, revealing increased resistance to fluconazole and voriconazole with the Y132F mutation. The research provides insights into the susceptibility of recombinant CYP51 from C. parapsilosis to azole drugs, which may help advance structure-directed antifungal discovery.
Article
Chemistry, Medicinal
Nicole M. R. McNeil, Eric W. J. Gates, Neda Firoozi, Nicholas J. Cundy, Jessica Leccese, Sarah Eisinga, Joel D. A. Tyndall, Gautam Adhikary, Richard L. Eckert, Jeffrey W. Keillor
Summary: The multifunctional protein tissue transglutaminase (TG2) plays a key role in protein crosslinking and intracellular G-protein functions, with implications in diseases and cancer stem cell survival. A recent study focused on developing covalent inhibitors to selectively target the enzyme active site of TG2, showing promising results in enhancing efficiency and affinity for TG2. Molecular modelling was used to understand the binding mode of the inhibitors, with the most efficient ones demonstrating isozyme selectivity, blocking GTP binding, and improved pharmacokinetic properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Joel D. A. Tyndall
Summary: The COVID-19 pandemic has highlighted scientists' ability to respond quickly to global challenges. This article presents the discovery of the orally available 3CL protease inhibitor S-217622 through structure-based drug design, screening, and optimization by Shionogi and Hokkaido University.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Aggie Lawer, Chelsea Tyler, Kiel Hards, Laura M. Keighley, Chen-Yi Cheung, Fabian Kierek, Simon Su, Siddharth S. Matikonda, Tyler McInnes, Joel D. A. Tyndall, Kurt L. Krause, Gregory M. Cook, Allan B. Gamble
Summary: We accomplished a revised total synthesis of aurachin D and evaluated the inhibitory activity against Mycobacterium tuberculosis cyt-bd oxidase and growth inhibition of Mtb. Several analogues showed nanomolar inhibition against Mtb cyt-bd oxidase and moderate growth inhibition against pathogenic Mtb.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Physical
Jiazhen Yin, Raahul Sharma, Joel D. A. Tyndall, Natasha L. Grimsey, Andrea J. Vernall
Summary: GPCR ligand prodrugs that can be released on demand have important applications in studying the consequences of GPCR activation or blockade. The development and characterization of a cannabinoid type 2 receptor agonist prodrug based on a photo caging moiety is described here. The prodrug showed rapid photolysis and good stability, but had significantly decreased binding affinity to the human cannabinoid type 2 receptor compared to the active parent ligand.
Article
Chemistry, Multidisciplinary
Tobias M. Bruetsch, Etienne Cotter, Daniel Lucena-Agell, Mariano Redondo-Horcajo, Carolina Davies, Bernhard Pfeiffer, Sandro Pagani, Simone Berardozzi, J. Fernando Diaz, John H. Miller, Karl-Heinz Altmann
Summary: In this study, five analogs of (-)-zampanolide (ZMP) were synthesized and their biochemical and cellular properties were evaluated. These analogs were derived from 13-desmethylene-(-)-zampanolide (DM-ZMP), which is as potent as ZMP in inhibiting cancer cell growth. Key steps in the synthesis of all compounds included the formation of a dioxabicyclo[15.3.1]heneicosane core and the establishment of the C(20) stereocenter. All modifications resulted in reduced cellular activity and microtubule-binding affinity compared to DM-ZMP, with varying degrees. The most potent analog, 2,3-dihydro-13-desmethylene zampanolide, showed cellular potency within a ninefold range of DM-ZMP.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Review
Biochemistry & Molecular Biology
Ian Liddle, Michelle Glass, Joel D. A. Tyndall, Andrea J. Vernall
Summary: X-ray crystallography and cryogenic electronic microscopy have made significant advancements in understanding the structure of GPCRs and designing ligands. Recent studies on cannabinoid receptors have enhanced our understanding of ligand binding sites and receptor residues that play a role in ligand selectivity.
RSC MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Sameek Singh, Ian Liddle, Christa Macdonald, Joel D. A. Tyndall, Michelle Glass, Andrea J. Vernall
Summary: CB2R is an important therapeutic target for pain and inflammatory disorders, and better understanding of GPCR location requires tools that can differentiate cell surface versus subcellular receptors.
AUSTRALIAN JOURNAL OF CHEMISTRY
(2021)
