Review
Pharmacology & Pharmacy
Xuesong Wang, Gerard J. P. van Westen, Laura H. Heitman, Adriaan P. IJzerman
Summary: G protein-coupled receptors (GPCRs) are the largest class of membrane proteins in the human genome, regulating various biological processes and serving as targets for a significant percentage of drugs on the market. Yeast serves as a useful model for studying GPCRs and offers opportunities for novel drug discovery.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Harmandeep Kaur, Veera Ganesh Yerra, Sri Nagarjun Batchu, Duc Tin Tran, M. D. Golam Kabir, Youan Liu, Suzanne L. Advani, Phelopater Sedrak, Laurette Geldenhuys, Karthik K. Tennankore, Penelope Poyah, Ferhan S. Siddiqi, Andrew Advani
Summary: In this study, a transcriptional profile of activated kidney fibroblasts and the GPCRs they express was established in mouse models of kidney disease. The marker Tcf21 and the GPCRs Adgra2 and S1pr3 were found to be highly expressed in these activated fibroblasts. This research provides new insights into potential therapeutic targets for treating CKD.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Leigh A. Stoddart, Laura E. Kilpatrick, Ross Corriden, Barrie Kellam, Stephen J. Briddon, Stephen J. Hill
Summary: The organization of G protein-coupled receptors at the plasma membrane has been a recent focus. Studies on the adenosine A(3) receptor and its mutant R108A reveal differences in membrane organization and downstream signaling, but both receptors can recruit beta-arrestin upon agonist stimulation, showing that effective G protein signaling is not necessary for membrane reorganization and beta-arrestin recruitment.
Review
Chemistry, Medicinal
Hyeonyeong Im, Ji-Hyun Park, Seowoo Im, Juhyeong Han, Kyungmin Kim, Yun-Hee Lee
Summary: The high incidence of obesity has led to an increased need to discover new therapeutic targets. Recent research has shown that G-protein coupled receptors (GPCRs) could be potential therapeutic targets to regulate adipose tissue metabolism.
ARCHIVES OF PHARMACAL RESEARCH
(2021)
Article
Microbiology
Yudan Lu, Xiaomei Zheng, Yu Wang, Lihui Zhang, Lixian Wang, Yu Lei, Tongcun Zhang, Ping Zheng, Jibin Sun
Summary: In this study, a workflow based on fluorescent-auxotrophic selection was developed for efficient evaluation of endogenous constitutive promoters in Aspergillus niger. Six endogenous promoters were characterized, and the PgpdAg promoter showed a 2.28-fold increase in activity compared to the frequently used PgpdAd promoter. The PgpdAg promoter was used to enhance the expression of the citrate transporter cexA, resulting in a 2.19-fold increase in transcription level and upregulation of genes involved in carbohydrate transport and metabolism. The overexpression of cexA and the upregulation of these genes led to a 2.48-fold increase in citric acid production compared to the parent strain.
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
Polymer Science
Kriti Kapil, Shirley Xu, Inseon Lee, Hironobu Murata, Seok-Joon Kwon, Jonathan S. Dordick, Krzysztof Matyjaszewski
Summary: Well-defined multifunctional copolymers with rhodamine B dye were synthesized by ATRP, enabling efficient and specific bioimaging of Staphylococcus aureus. The combination of multifunctional polymeric dyes and strain-specific Ab or CBD showed enhanced fluorescence and target selectivity, making them potential biosensors for the detection of target DNA, protein, or bacteria.
Review
Cell Biology
Haoran Jiang, Daniella Galtes, Jialu Wang, Howard A. Rockman
Summary: This review explores the signaling pathways, dynamic structures, and physiological relevance of the three most important GPCR signaling effectors in the cardiovascular system: heterotrimeric G proteins, GPCR kinases (GRKs), and 8-arrestins. It summarizes their prominent roles in GPCR pharmacology before transitioning into less well-explored areas. The application of new technologies has contributed to an increasing understanding of GPCR structure and downstream effectors.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Article
Pharmacology & Pharmacy
Estefania Moreno, Nil Casajuana-Martin, Michael Coyle, Baruc Campos Campos, Ewa Galaj, Claudia Llinas del Torrent, Arta Seyedian, William Rea, Ning-Sheng Cai, Alessandro Bonifazi, Benjamin Floran, Zheng-Xiong Xi, Xavier Guitart, Vicent Casado, Amy H. Newman, Christopher Bishop, Leonardo Pardo, Sergi Ferre
Summary: This study provides evidence that heteromerization of G protein-coupled receptors (GPCRs), specifically dopamine D1 and D3 receptors, can influence the pharmacological properties of selective ligands. In vivo experiments support the involvement of D1R-D3R heteromers in the development of L-DOPA-induced dyskinesia in Parkinson's disease, suggesting the potential of targeting GPCR heteromers for drug development.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Juergen Einsiedel, Maximilian F. Schmidt, Harald Huebner, Peter Gmeiner
Summary: A broadly applicable synthesis method was developed for peptides incorporating mixed disulfides between cysteine and homocysteine and cysteamine. The method was successfully applied to pharmacologically relevant GPCR ligands and showed covalent binding to neurotensin receptor 1 in a radioligand depletion study.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Matej Gazdarica, Judith Noda, Oleh Durydivka, Vendula Novosadova, Ken Mackie, Jean-Philippe Pin, Laurent Prezeau, Jaroslav Blahos
Summary: CB1R signaling is regulated by receptor desensitization and the protein SGIP1, which plays an important role in controlling CB1R function and its involvement in pathological conditions.
JOURNAL OF NEUROCHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Bui San Thai, Ling Yeong Chia, Anh T. N. Nguyen, Chengxue Qin, Rebecca H. Ritchie, Dana S. Hutchinson, Andrew Kompa, Paul J. White, Lauren T. May
Summary: Heart failure remains a significant cause of morbidity and mortality worldwide. Current treatment options have limitations, leading to many patients progressing to advanced stages. Exploration of novel therapeutics targeting G protein-coupled receptors (GPCRs) has shown promise, but efficacy and unwanted effects remain as challenges.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Canyong Guo, Lingyun Yang, Zhijun Liu, Dongsheng Liu, Kurt Wuthrich
Summary: Eight hundred and twenty-six human G protein-coupled receptors (GPCRs) play a significant role in mediating the actions of hormones, neurotransmitters, and drugs. Studying the structure and dynamics of GPCRs in lipid bilayer environments is crucial for understanding their functionality and developing new drugs. This study incorporates the A(2A) adenosine receptor into lipid nanodiscs, providing a detergent-free environment for structural studies using NMR. The findings demonstrate the stability and mimicry of the lipid nanodisc and LMNG/CHS micelles in preserving the overall fold and local structure of the receptor.
Review
Pharmacology & Pharmacy
Mydirah Littlepage-Saunders, Michael J. Hochstein, Doris S. Chang, Kari A. Johnson
Summary: Dopamine transmission in the striatum is regulated by various G protein-coupled receptors (GPCRs) that bind neuromodulators, including dopamine itself. These GPCRs can modulate dopamine release by acting on different components of the dopaminergic circuitry and can have distinct effects on behavior and psychoactive drug actions. This review discusses the mechanisms by which GPCRs regulate dopaminergic transmission and their relevance to the effects of psychoactive drugs on physiology and behavior.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Thian-Sze Wong, Guangzhi Li, Shiliang Li, Wei Gao, Geng Chen, Shiyi Gan, Manzhan Zhang, Honglin Li, Song Wu, Yang Du
Summary: Neuropsychiatric disorders are complex and have various causes. Finding effective treatment targets is difficult due to the heterogeneous nature of these diseases. However, the growing knowledge of G protein-coupled receptors (GPCRs) provides a potential avenue for drug discovery. Understanding the molecular mechanisms and structures of GPCRs can aid in the development of effective drugs. This review provides an overview of the role of GPCRs in neurodegenerative and psychiatric diseases, highlights new opportunities for GPCR targets, and discusses recent progress in GPCR drug development.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2023)
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)
Review
Chemistry, Multidisciplinary
Eszter Kozma, Marton Bojtar, Peter Kele
Summary: Photoresponsive materials with spatiotemporal control have significant potential in targeted cancer therapies. The combination of photoactivatable approaches with bioorthogonal chemistry enhances precision and may have profound implications in treating disperse/diffuse tumors. The intensified research in bioorthogonally assisted phototherapy is justified by the anticipated growth of further developments in the field, making a timely summary of the state of the art necessary.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Neurosciences
Kenneth A. Jacobson, Balaram Pradhan, Zhiwei Wen, Asmita Pramanik
Summary: The discovery and clinical implementation of adenosine, P2Y and P2X receptor modulators have advanced significantly in the past 50 years. Although previous clinical trials of selective ligands have not been successful, there is now a renewed focus on new disease conditions and the development of more selective compounds, as well as the elucidation of new receptor and enzyme structures.
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
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)
Article
Pharmacology & Pharmacy
Paola Orlandi, Marta Banchi, Francesca Vaglini, Marco Carli, Stefano Aringhieri, Arianna Bandini, Carla Pardini, Cristina Viaggi, Michele Lai, Greta Ali, Alessandra Ottani, Eleonora Vandini, Patrizia Guidi, Margherita Bernardeschi, Veronica La Rocca, Giulio Francia, Gabriella Fontanini, Mauro Pistello, Giada Frenzilli, Daniela Giuliani, Marco Scarselli, Guido Bocci
Summary: This study investigates the role of MC4R in melanoma and the use of the selective antagonist ML in combination with vemurafenib. The results show that ML can inhibit melanoma cell proliferation and induce apoptosis through the inhibition of ERK1/2 phosphorylation and reduction of BCL-XL expression. The combination of vemurafenib and ML exhibits a synergistic effect in vitro and inhibits tumor growth in vivo without causing adverse effects.
BIOCHEMICAL PHARMACOLOGY
(2024)
Article
Pharmacology & Pharmacy
Conor J. Bloxham, Katina D. Hulme, Fabrizio Fierro, Christian Fercher, Cassandra L. Pegg, Shannon L. O'Brien, Simon R. Foster, Kirsty R. Short, Sebastian G. B. Furness, Melissa E. Reichelt, Masha Y. Niv, Walter G. Thomas
Summary: Bitter taste receptors (T2Rs) are a type of G protein-coupled receptors that allow humans to detect aversive and toxic substances. This study characterized the functional properties of previously identified T2Rs in human cardiac tissues and their naturally occurring polymorphisms. The results showed differences in signaling among different T2R variants, and revealed a potential association between the T2R50 Tyr203 variant and cardiovascular disease.
BIOCHEMICAL PHARMACOLOGY
(2024)
Article
Pharmacology & Pharmacy
Lu Chen, Huanying Shi, Wenxin Zhang, Yongjun Zhu, Haifei Chen, Zimei Wu, Huijie Qi, Jiafeng Liu, Mingkang Zhong, Xiaojin Shi, Tianxiao Wang, Qunyi Li
Summary: This study demonstrates that Carfilzomib exhibits potent anti-tumor activity against esophageal squamous cell carcinoma (ESCC) by triggering mitochondrial apoptosis and reprogramming cellular metabolism. It has been identified that activating transcription factor 3 (ATF3) plays a crucial role as a cellular target in ESCC cells treated with Carfilzomib. Overexpression of ATF3 effectively counteracts the effects of Carfilzomib on ESCC cell proliferation, apoptosis, and metabolic reprogramming. Furthermore, ATF3 mediates the anti-tumor activity of Carfilzomib, suggesting its potential as a therapeutic agent for ESCC.
BIOCHEMICAL PHARMACOLOGY
(2024)
Review
Pharmacology & Pharmacy
Xing Zhang, Xiang Li, Ran Xia, Hong-Sheng Zhang
Summary: This review summarizes recent progress on the mechanisms of ferroptosis resistance in cancer and highlights the role of redox status and metabolism. Combination therapy for ferroptosis has great potential in treating resistant malignant tumors.
BIOCHEMICAL PHARMACOLOGY
(2024)
