Review
Pharmacology & Pharmacy
Ilana B. Kotliar, Emily Lorenzen, Jochen M. Schwenk, Debbie L. Hay, Thomas P. Sakmar
Summary: G protein-coupled receptors (GPCRs) interact with a variety of membrane proteins, but the extent and mechanisms of these interactions are not well understood. RAMPs, a class of GPCR-interacting proteins, have been extensively studied. Recent research suggests that GPCR-RAMP interactions may be more widespread than previously thought. This review summarizes the latest techniques for discovering GPCR-RAMP interactions and their functional consequences, and discusses future research prospects.
PHARMACOLOGICAL REVIEWS
(2023)
Article
Multidisciplinary Sciences
Xudong Wang, Chris Neale, Soo-Kyung Kim, William A. Goddard, Libin Ye
Summary: Understanding the roles of intermediate states in GPCR signaling is crucial for studying the activation processes. In this study, conformation-biased mutants were used to enrich the populations of discrete states along the activation pathway of A(2A)R. The results reveal important structural interactions and propose a GPCR activation process modulated by these interactions.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Hannes Schihada, Rawan Shekhani, Gunnar Schulte
Summary: The research team developed and validated eight G protein sensors that can measure the activity of all major families of G proteins, along with a protocol to identify constitutive GPCR or G protein signaling in live cells.
Article
Multidisciplinary Sciences
Vaithish Velazhahan, Ning Ma, Gaspar Pandy-Szekeres, Albert J. Kooistra, Yang Lee, David E. Gloriam, Nagarajan Vaidehi, Christopher G. Tate
Summary: GPCRs are divided into six classes, with structures of vertebrate GPCRs well understood but not of fungal class D GPCRs. This study reveals the structure of a class D GPCR in yeast and its coupling to G proteins, providing a template for the design of drugs to treat fungal diseases.
Article
Biochemistry & Molecular Biology
Nicole Ahrens, Enno Aeissen, Anka Lippe, Ulrike Janssen-Bienhold, Jens Christoffers, Karl-Wilhelm Koch
Summary: GRKs deactivate G-protein-coupled receptors through phosphorylation, with four orthologous GRKs participating in the deactivation of rod and cone opsins in photoreceptor cells. GRKs have consensus sites for lipid modification, allowing the attachment of isoprenoids. A semichemical approach was used to study the incorporation of a farnesyl moiety into a GRK and its cellular consequences.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Jeremie Topin, Cedric Bouysset, Jody Pacalon, Yiseul Kim, Mee-Ra Rhyu, Sebastien Fiorucci, Jerome Golebiowski
Summary: Bitter taste receptors (TAS2Rs) are a poorly understood subgroup of G protein-coupled receptors (GPCRs), with their experimental structure yet to be determined and key-residues controlling their function mostly unknown. Researchers designed an integrative approach to improve comparative modeling of TAS2Rs.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Multidisciplinary Sciences
Arne Thies, Vikram Sunkara, Sourav Ray, Hanna Wulkow, M. Oezguer Celik, Fatih Yergoez, Christof Schuette, Christoph Stein, Marcus Weber, Stefanie Winkelmann
Summary: We have successfully designed, synthesized, and tested the prototype opioid painkiller NFEPP, which does not have adverse side effects. The design process was based on mathematical modeling of interactions between G-protein coupled receptors (GPCRs) and ligands, considering the different functions of GPCRs under pathological and healthy conditions. Additionally, we have proposed a novel stochastic model of GPCR function that takes into account intracellular dissociation of G-protein subunits and modulation of plasma membrane calcium channels, which depend on the parameters of inflamed and healthy tissue (pH, radicals). The model has been validated using in vitro experimental data for NFEPP and fentanyl at different pH values and radical concentrations.
SCIENTIFIC REPORTS
(2023)
Article
Chemistry, Medicinal
Dilip K. Tosh, Maggie M. Calkins, Marko S. Ivancich, Hailey A. Bock, Ryan G. Campbell, Sarah A. Lewicki, Eric Chen, Zhan-Guo Gao, John D. Mccorvy, Kenneth A. Jacobson
Summary: Derivatives of (N)-Methanocarba adenosine were modified to target 5-HT2B serotonin receptors as antagonists, showing affinity enhancement with the bicyclic ring system. Compound 43 (MRS7925) exhibited potential for anti-fibrotic therapy due to its affinity and moderate 5-HT2BR binding selectivity. The compounds also demonstrated dual action as 5-HT2B antagonists and A(1)AR agonists.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Andrew B. Kleist, Shawn Jenjak, Andrija Sente, Lauren J. Laskowski, Martyna Szpakowska, Maggie M. Calkins, Emilie Anderson, Lisa M. McNally, Raimond Heukers, Vladimir Bobkov, Francis C. Peterson, Monica A. Thomas, Andy Chevigne, Martine J. Smit, John D. McCorvy, M. Madan Babu, Brian F. Volkman
Summary: NMR experiments on ACKR3 revealed that the recruitment of beta-arrestins is associated with conformational exchange at key regions of the receptor, and identified an allosteric hub in the core receptor that coordinates transitions among different conformational states, guiding beta-arrestin recruitment.
Article
Chemistry, Multidisciplinary
Hsin-Yung Yen, Idlir Liko, Wanling Song, Parth Kapoor, Fernando Almeida, Joanna Toporowska, Karolina Gherbi, Jonathan T. S. Hopper, Steven J. Charlton, Argyris Politis, Mark S. P. Sansom, Ali Jazayeri, Carol Robinson
Summary: This study presents a mass spectrometry-based approach to investigate the biased signaling and allosteric modulation of the beta(1)-adrenergic receptor in response to different ligands. The researchers discovered that isoprenaline can act as a biased agonist and that endogenous zinc ions enhance the binding between the receptor and G(s) proteins.
Article
Chemistry, Multidisciplinary
Jordan M. Mattheisen, Chris Limberakis, Roger B. Ruggeri, Matthew S. Dowling, Christopher W. am Ende, Emilie Ceraudo, Thomas Huber, Christopher L. McClendon, Thomas P. Sakmar
Summary: We developed a strategy to covalently tether drug fragments adjacent to allosteric sites in GPCRs to enhance their potency and enable fragment-based drug screening in cell-based systems.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biology
Oliver Fleetwood, Jens Carlsson, Lucie Delemotte
Summary: The study elucidated how ligands stabilize the conformation of G protein-coupled receptors by tuning protein microswitches, influencing the activation state of the signaling pathway. Ligand binding induces a shift of the receptor towards active-like states, and different ligands can induce similar conformational states.
Review
Biochemistry & Molecular Biology
Dehua Yang, Qingtong Zhou, Viktorija Labroska, Shanshan Qin, Sanaz Darbalaei, Yiran Wu, Elita Yuliantie, Linshan Xie, Houchao Tao, Jianjun Cheng, Qing Liu, Suwen Zhao, Wenqing Shui, Yi Jiang, Ming-Wei Wang
Summary: Recent progress in understanding the structure-function relationships of G protein-coupled receptors has accelerated drug development significantly. This article aims to provide a comprehensive overview of this important field to a broader readership interested in drug discovery.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2021)
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
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
Biochemistry & Molecular Biology
Kiran S. Toti, Ryan G. Campbell, Hobin Lee, Veronica Salmaso, R. Rama Suresh, Zhan-Guo Gao, Kenneth A. Jacobson
Summary: Adenosine receptor (AR) ligands are being developed for the treatment of metabolic, cardiovascular, neurological, and inflammatory diseases and cancer. Fluorescent antagonist ligands were synthesized and screened for their affinities and selectivity towards different AR subtypes, showing potential as live cell or in vivo imaging tools and/or therapies.
PURINERGIC SIGNALLING
(2023)
Book Review
Chemistry, Medicinal
Kenneth A. Jacobson
Review
Biochemistry & Molecular Biology
Zhan-Guo Gao, John A. Auchampach, Kenneth A. Jacobson
Summary: Efforts to understand pharmacological differences between GPCR species homologues are generally not pursued in drug development. However, studying the pharmacological properties of the A(3) adenosine receptor (AR) is critical for understanding its biological functions. Pharmacological characterization of recombinant A(3)ARs from different species has been conducted.
PURINERGIC SIGNALLING
(2023)
Article
Biochemistry & Molecular Biology
Cuiying Xiao, Oksana Gavrilova, Naili Liu, Sarah A. Lewicki, Marc L. Reitman, Kenneth A. Jacobson
Summary: Some drugs act on adenosine receptors (ARs) to produce effects, as demonstrated in mouse hypothermia experiments. Four drugs (dipyridamole, nimodipine, cilostazol, cyclosporin A) increased adenosine-induced hypothermia, while two drugs (cannabidiol, canrenoate) did not cause hypothermia. Four other drugs (nifedipine, ranolazine, ketamine, ethanol) caused hypothermia through non-adenosinergic mechanisms. Zinc chloride caused hypothermia and hypoactivity, which was reduced in mice lacking ARs. Interestingly, the antidepressant amitriptyline caused amplified hypothermia in mice lacking ARs. These findings suggest potential repurposing of adenosine-modulating drugs based on their effects on AR activation.
PURINERGIC SIGNALLING
(2023)
Article
Biochemistry & Molecular Biology
Federica Cherchi, Martina Venturini, Giada Magni, Mirko Scortichini, Kenneth A. Jacobson, Anna Maria Pugliese, Elisabetta Coppi
Summary: Recent studies have focused on the analgesic effects of adenosine and its receptors in chronic pain models. The A(3)AR receptor subtype has been found to reduce pro-nociceptive N-type Ca2+ channels, leading to inhibition of post inflammatory visceral hypersensitivity. This study investigates the effect of a previously reported irreversible A(3)AR agonist, ICBM, on Ca2+ currents in rat DRG neurons. The findings suggest that covalent A(3)AR agonists such as ICBM may offer a longer-lasting and more efficient strategy for chronic pain control compared to reversible A(3)AR agonists, but further pre-clinical studies are needed to address potential limitations and adverse effects.
PURINERGIC SIGNALLING
(2023)
Editorial Material
Pharmacology & Pharmacy
Francisco Ciruela, Kenneth A. Jacobson
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Multidisciplinary Sciences
Zhan-Guo Gao, Ian M. Levitan, Asuka Inoue, Qiang Wei, Kenneth A. Jacobson
Summary: Protein kinase C (PKC) isoforms can enhance A(2B) adenosine receptor (AR)-mediated cAMP accumulation through activation by phorbol 12-myristate 13-acetate (PMA), but do not enhance beta(2)-adrenergic receptor-mediated cAMP accumulation. PKC activation can also induce cAMP accumulation by activating A(2B)AR with high or low E-max. These findings are important for understanding the functions of A(2B)AR and PKC.
Article
Chemistry, Medicinal
Jung-Eun Park, Hobin Lee, Paola Oliva, Klara Kirsch, Bora Kim, Jong Il Ahn, Celeste N. Alverez, Snehal Gaikwad, Kristopher W. Krausz, Robert O'Connor, Ganesha Rai, Anton Simeonov, Beverly A. Mock, Frank J. Gonzalez, Kyung S. Lee, Kenneth A. Jacobson
Summary: Polo-like kinase 1 (Plk1) is an attractive target for anticancer drug discovery due to its widely upregulated activity in various human cancers. In addition to the kinase domain, the C-terminal noncatalytic polo-box domain (PBD) has emerged as an alternative target for developing inhibitors. Triazoloquinazolinone-derived inhibitors effectively block Plk1 with improved affinity and drug-like properties. Further derivatization is needed to improve the stability of these inhibitors for the development of therapeutics against Plk1-addicted cancers.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Qasim Shah, Zahid Hussain, Bilal Ahmad Khan, Kenneth A. Jacobson, Jamshed Iqbal
Summary: The study investigates the potency of P2X7 receptor antagonists and their relationship with cancer, revealing five compounds with strong selective inhibitory effects. These compounds exhibit varying cell viability and induction of apoptosis in transfected and non-transfected cell lines.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Dilip K. Tosh, Maggie M. Calkins, Marko S. Ivancich, Hailey A. Bock, Ryan G. Campbell, Sarah A. Lewicki, Eric Chen, Zhan-Guo Gao, John D. Mccorvy, Kenneth A. Jacobson
Summary: Derivatives of (N)-Methanocarba adenosine were modified to target 5-HT2B serotonin receptors as antagonists, showing affinity enhancement with the bicyclic ring system. Compound 43 (MRS7925) exhibited potential for anti-fibrotic therapy due to its affinity and moderate 5-HT2BR binding selectivity. The compounds also demonstrated dual action as 5-HT2B antagonists and A(1)AR agonists.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Katarina Mihajlovic, Marija Adzic Bukvic, Milorad Dragic, Mirko Scortichini, Kenneth A. Jacobson, Nadezda Nedeljkovic
Summary: In this in vitro study, three novel cytosine-derived alpha,beta-methylene diphosphonates (MRS4598, MRS4552, and MRS4602) were tested for their potency in inhibiting CD73 activity and attenuating reactive astrocyte phenotype. The results showed that all compounds exhibited concentration-dependent inhibition of CD73 activity with high inhibitory potency and binding capacity. Among them, MRS4598 was the most effective in inhibiting CD73 activity and inducing reactive astrocyte phenotype inhibition, making it a promising tool for the treatment of neurodegeneration and neuroinflammation.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Zhiwei Wen, Asmita Pramanik, Sarah A. Lewicki, Young-Hwan Jung, Zhan-Guo Gao, John C. R. Randle, Chunxia Cronin, Zhoumou Chen, Luigino A. Giancotti, Gregory S. Whitehead, Bruce T. Liang, Sylvie Breton, Daniela Salvemini, Donald N. Cook, Kenneth A. Jacobson
Summary: P2Y(14) receptor is activated by extracellular UDP-glucose, promoting inflammation in various tissues. Selective P2Y(14)R antagonists could be useful for inflammatory and metabolic diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Hai-Jun Zhang, Michal Ociepa, Molhm Nassir, Bin Zheng, Sarah A. Lewicki, Veronica Salmaso, Helay Baburi, Jessica Nagel, Salahuddin Mirza, Haneen Al-Hroub, Beatriz Bueschbell, Olga Perzanowska, Ziqin Lin, Michael A. Schmidt, Martin D. Eastgate, Kenneth A. Jacobson, Christa E. Mueller, Joanna Kowalska, Jacek Jemielity, Phil S. Baran
Summary: Nucleoside diphosphates and triphosphates have a profound impact on biochemistry, but their usage as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hindered by their rapid metabolism in the body. This study demonstrates the development of a modular, reagent-based platform that allows the stereocontrolled and scalable synthesis of pure stereoisomers of nucleoside thioisosteres, which can have significant effects on ligand-receptor interactions.
Article
Chemistry, Medicinal
Eline Pottie, R. Rama Suresh, Kenneth A. Jacobson, Christophe P. Stove
Summary: This study aimed to explore inverse agonism at A(3)AR using two engineered cell lines and NanoBiT technology. The previously established inverse agonist PSB-10 showed inverse agonism in one assay but not in another. Further experiments confirmed the specificity and reversibility of this observation. Evaluation of presumed neutral antagonists revealed their concentration-dependent inverse agonism in the A(3)AR-βarr2 recruitment assay.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Chemistry, Medicinal
Dilip K. Tosh, Courtney L. Fisher, Veronica Salmaso, Tina C. Wan, Ryan G. Campbell, Eric Chen, Zhan-Guo Gao, John A. Auchampach, Kenneth A. Jacobson
Summary: (N)-Methanocarba adenosine derivatives were modified to form macrocyclic A(3) adenosine receptor agonists. These macrocycles retained affinity and had a spatially proximal orientation on the receptor. C2-Arylethynyl-linked macrocycle 19 showed higher selectivity for A(3) adenosine receptor compared to 2-ether-linked macrocycle 12.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)