Review
Pharmacology & Pharmacy
Ben Jones
Summary: GLP-1 receptor agonists are effective treatments for type 2 diabetes by stimulating insulin release and promoting weight loss, but their main side effect is nausea. Recent studies suggest that biased GLP-1 agonists may achieve enhanced anti-hyperglycaemic efficacy by avoiding receptor desensitization and downregulation, particularly through reduced beta-arrestin recruitment, although more human data is needed for confirmation.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Liliane El Eid, Christopher A. Reynolds, Alejandra Tomas, Ben Jones
Summary: This article reviews the structure and activation of GLP-1 receptor (GLP-1R), providing structural evidence for biased agonism and describing important networks associated with this phenomenon. The authors survey current biased agonists and multi-agonists at different stages of development and discuss the findings related to non-synonymous genomic variants of GLP-1R. They propose that studying the effect of GLP-1R polymorphisms on receptor dynamics and pharmacology in response to biased agonists could lead to precision medicine approaches and the development of novel therapeutics.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Cell Biology
Michael Ippolito, Jeffrey L. Benovic
Summary: β-adrenergic receptors consist of three subtypes and play important roles in regulating physiological processes. Developing biased agonists could potentially enhance treatment efficacy for diseases.
CELLULAR SIGNALLING
(2021)
Review
Endocrinology & Metabolism
Alessandra Puddu, Davide Maggi
Summary: GLP-1, produced in intestinal L cells, plays a key role in glucose homeostasis and is widely used in Type 2 Diabetes treatment. Its effectiveness is linked to GLP-1R activation, which is present in various tissues. In addition to beta cells, GLP-1 also has extra-pancreatic effects, regulated through co-localization with caveolin-1.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Article
Pharmacology & Pharmacy
Amaara Marzook, Shiqian Chen, Phil Pickford, Maria Lucey, Yifan Wang, Ivan R. Jr Jr Correa, Johannes Broichhagen, David J. Hodson, Victoria Salem, Guy A. Rutter, Tricia M. Tan, Stephen R. Bloom, Alejandra Tomas, Ben Jones
Summary: In this study, differences between the GLP-1R agonists P5 and exendin-F1 were examined through various assays, revealing that while exendin-F1 showed lower acute efficacy, it demonstrated greater effects on insulin secretion and sustained anti-hyperglycaemic efficacy in mice compared to P5.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Bingfa Sun, Francis S. Willard, Dan Feng, Jorge Alsina-Fernandez, Qi Chen, Michal Vieth, Joseph D. Ho, Aaron D. Showalter, Cynthia Stutsman, Liyun Ding, Todd M. Suter, James D. Dunbar, John W. Carpenter, Faiz Ahmad Mohammed, Eitaro Aihara, Robert A. Brown, Ana B. Bueno, Paul J. Emmerson, Julie S. Moyers, Tong Sun Kobilka, Matthew P. Coghlan, Brian K. Kobilka, Kyle W. Sloop
Summary: Tirzepatide is a dual incretin receptor agonist that improves glucose control and body weight regulation in type 2 diabetes mellitus. Mechanistic pharmacology studies combined with cryogenic electron microscopy have provided insights into the structural basis and interactions of Tirzepatide with GIPR and GLP-1R.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Pharmacology & Pharmacy
Eamonn Kelly, Alexandra Conibear, Graeme Henderson
Summary: In ligand bias, different agonist drugs activate distinct signaling pathways, leading to different therapeutic and adverse effects. While it was believed that selectively activating the G protein-dependent pathway of the mu-opioid receptor would result in effective analgesia without adverse effects, recent data suggest that most effects are mediated by this pathway and some drugs described as biased may actually be low-intrinsic-efficacy agonists. This review discusses the current understanding of bias at the mu-opioid receptor and other opioid receptor subtypes.
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY
(2023)
Article
Endocrinology & Metabolism
Phil Pickford, Maria Lucey, Roxana-Maria Rujan, Emma Rose McGlone, Stavroula Bitsi, Fiona B. Ashford, Ivan R. Correa, David J. Hodson, Alejandra Tomas, Giuseppe Deganutti, Christopher A. Reynolds, Bryn M. Owen, Tricia M. Tan, James Minnion, Ben Jones, Stephen R. Bloom
Summary: By reducing 13-arrestin-2 recruitment, this study found that the duration of glucose-lowering action can be prolonged, increasing the therapeutic efficacy of GLP-1R/GCGR co-agonists. Retaining potential benefits of GCGR agonism, the tested compounds showed only partial agonism in both pathways.
MOLECULAR METABOLISM
(2021)
Article
Multidisciplinary Sciences
Li-Hua Zhao, Qian He, Qingning Yuan, Yimin Gu, Xinheng He, Hong Shan, Junrui Li, Kai Wang, Yang Li, Wen Hu, Kai Wu, Jianhua Shen, H. Eric Xu
Summary: This study reports a new binding mode between a G protein and its receptor, involving a specific small-molecule agonist. The high-resolution structure of the complex is determined, providing insights for designing small-molecule agonists for class B G-protein-coupled receptors.
Article
Multidisciplinary Sciences
Li-Hua Zhao, Qian He, Qingning Yuan, Yimin Gu, Xinheng He, Hong Shan, Junrui Li, Kai Wu, Yang Li, Wen Hu, Kai Wu, Jianhua Shen, H. Eric Xu
Summary: A study reports an orally available small-molecule agonist that binds between a G protein and its receptor, and characterizes this new binding mode.
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)
Review
Cell Biology
Qiwen Liao, Richard D. Ye
Summary: G protein-coupled chemoattractant receptors, such as FPR2, play a crucial role in leukocyte chemotaxis and have diverse cellular functions in response to various agonists. Recent studies have provided insights into the structural and conformational aspects of FPR2, revealing its ability to bind different ligands in different poses.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Article
Cell Biology
Krysten E. Ferraino, Natalie Cora, Celina M. Pollard, Anastasiya Sizova, Jennifer Maning, Anastasios Lymperopoulos
Summary: Angiotensin II (AngII) utilizes AT1R and AT2R G protein-coupled receptors to exert physiological effects, particularly impacting cardiovascular homeostasis. AT1R signaling mobilizes multiple signal transducers inside cells, with Gq/11 proteins and ?-arrestins specifically activated to promote aldosterone synthesis and secretion in the adrenal cortex. "Biased" signaling refers to preferential activation of one signaling pathway over others downstream of the same receptor, with therapeutic relevance in selectively promoting beneficial effects over detrimental consequences.
CELLULAR SIGNALLING
(2021)
Review
Endocrinology & Metabolism
David C. D. Hope, Matthew L. Vincent, Tricia M. M. Tan
Summary: Obesity and Type 2 diabetes are global health challenges, with potential treatment options such as co-agonists showing promise in improving efficacy and reducing adverse effects. Further research is needed to guide the safe, effective, and personalized use of GLP-1/glucagon co-agonists in targeting weight loss and metabolic disease in the future.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Article
Pharmacology & Pharmacy
Maria Buur Nordskov Gabe, Laerke Smidt Gasbjerg, Sarina Gadgaard, Peter Lindquist, Jens Juul Holst, Mette Marie Rosenkilde
Summary: This study investigates the regulatory role of the GLP-2 system in the gut and bones by studying the effects of N-terminal truncations of human GLP-2 peptides on GLP-2 receptor activity and selectivity. The results show that the N-terminus of GLP-2 is crucial for GLP-2 receptor activity and selectivity. These findings provide a foundation for the development of tool compounds for further characterization of the GLP-2 system.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Sanaz Darbalaei, Ru-lue Chang, Qing-tong Zhou, Yan Chen, An-tao Dai, Ming-wei Wang, De-hua Yang
Summary: The paradigm of one drug against multiple targets, known as unimolecular polypharmacology, has shown promising results in the treatment of type 2 diabetes and obesity by targeting two or three specific receptors. By studying agonist efficacy and signaling patterns, this study reveals the crucial residue networks involved in agonist-mediated receptor activation, providing insights for the rational design of biased drug leads.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Pharmacology & Pharmacy
Ahmed Haider, Xiaoyun Deng, Olivia Mastromihalis, Stefanie K. Pfister, Troels E. Jeppesen, Zhiwei Xiao, Vi Pham, Shaofa Sun, Jian Rong, Chunyu Zhao, Jiahui Chen, Yinlong Li, Theresa R. Connors, April T. Davenport, James B. Daunais, Vahid Hosseini, Wenqing Ran, Arthur Christopoulos, Lu Wang, Celine Valant, Steven H. Liang
Summary: This study aimed to develop a suitable M4 PET ligand for the non-invasive visualization of M4 in the brain. The compound 12 was identified as a subtype-selective positive allosteric modulator (PAM) and its radiofluorinated analogue showed moderate specificity in rodent brain sections. However, in non-human primates and humans, the presence of carbachol did not improve the specificity and selectivity of the radioligand.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Biochemistry & Molecular Biology
Sabrina N. Rahman, Daniel A. McNaught-Flores, Yara Huppelschoten, Daniel da Costa Pereira, Arthur Christopoulos, Rob Leurs, Christopher J. Langmead
Summary: The human histamine H3 receptor is expressed in the CNS and regulates the synthesis and release of histamine and neurotransmitters. It is associated with CNS disorders and its isoforms display variations in intracellular loop 3. The mechanisms of biased agonism at these isoforms remain unknown.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Pharmacology & Pharmacy
Ye Jiang, Mahmuda Yeasmin, Arisbel B. Gondin, Arthur Christopoulos, Celine Valant, Wessel A. C. Burger, David M. Thal
Summary: This study investigated the activation of individual G protein subfamilies and downstream signaling pathways of compounds 6A and 7A at the M-2 mAChR. The results showed that M-2 mAChR primarily couples to Galpha(i/o) and Galpha(s), but no Galpha(i) bias was detected for compounds 6A and 7A. This highlights the importance of cellular background in classifying new ligands.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Pharmacology & Pharmacy
Ayame Saito, Sadia Alvi, Celine Valant, Arthur Christopoulos, Simona E. Carbone, Daniel P. Poole
Summary: The enteric nervous system plays a crucial role in regulating gastrointestinal motility. Disrupted enteric nervous system activity can lead to dysmotility. Pharmacological treatment options for dysmotility involve targeting G protein-coupled receptors (GPCRs) expressed by enteric nervous system neurons. Current drugs that target GPCRs for motility disorders have drawbacks such as significant side-effects and a loss of physiological tone. Allosteric modulation of GPCRs, which bind to a distinct site from the endogenous ligand, may provide effective relief from motility disorders while minimizing side-effects.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Endocrinology & Metabolism
Brian P. Cary, Xin Zhang, Jianjun Cao, Rachel M. Johnson, Sarah J. Piper, Elliot J. Gerrard, Denise Wootten, Patrick M. Sexton
Summary: G protein-coupled receptors (GPCRs), particularly the B1 class, play a critical role in maintaining homeostasis and are important drug targets. Recent advances in cryo-electron microscopy have provided valuable insights into the structure and dynamics of these receptors, which contribute to our understanding of their functions.
Article
Multidisciplinary Sciences
Yan Chen, Qingtong Zhou, Jiang Wang, Youwei Xu, Yun Wang, Jiahui Yan, Yibing Wang, Qi Zhu, Fenghui Zhao, Chenghao Li, Chuan-Wei Chen, Xiaoqing Cai, Ross A. . D. Bathgate, Chun Shen, H. Eric Xu, Dehua Yang, Hong Liu, Ming-Wei Wang
Summary: The authors reveal the ligand-binding modes and key determinants of peptidomimetic agonism and subtype selectivity through cryo-EM structures. This study provides insights into ligand recognition and subtype selectivity among class A G protein-coupled receptors, and expands the knowledge of signaling mechanisms in the insulin superfamily.
NATURE COMMUNICATIONS
(2023)
Review
Pharmacology & Pharmacy
Jo-Anne Baltos, Pablo M. Casillas-Espinosa, Ben Rollo, Karen J. Gregory, Paul J. White, Arthur Christopoulos, Patrick Kwan, Terence J. O'Brien, Lauren T. May
Summary: Epilepsy, a serious neurological condition, affects millions of people worldwide. Current pharmacotherapy only successfully controls seizures in about 70% of epilepsy patients, and many suffer from psychiatric and physical comorbidities. Adenosine, a natural substance, has shown potential as an anti-epileptic agent through its receptor activation. Recent advances have also shown that adenosine receptors can modulate epilepsy-associated comorbidities. This review provides an accessible resource on the use of the adenosine system as a therapeutic target for epilepsy and its associated comorbidities.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Correction
Biochemistry & Molecular Biology
Alexander S. Powers, Vi Pham, Wessel A. C. Burger, Geoff Thompson, Yianni Laloudakis, Nicholas W. Barnes, Patrick M. Sexton, Steven M. Paul, Arthur Christopoulos, David M. Thal, Christian C. Felder, Celine Valant, Ron O. Dror
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Alexander S. Powers, Vi Pham, Wessel A. C. Burger, Geoff Thompson, Yianni Laloudakis, Patrick M. Sexton, Steven M. Paul, Arthur Christopoulos, David M. Thal, Christian C. Felder, Celine Valant, Ron O. Dror
Summary: The selectivity of a drug for target receptors is crucial but challenging when the receptors are similar. Serendipitous discovery of ligands that stimulate target receptors more strongly than closely related receptors provides a solution. This study reveals the structural basis for the efficacy-driven selectivity of xanomeline, a clinical drug candidate, between closely related muscarinic acetylcholine receptors (mAChRs), using atomic-level simulations. The results suggest strategies for rational design of ligands achieving efficacy-driven selectivity for G-protein-coupled receptors.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Pierre Matricon, Anh T. N. Nguyen, Duc Duy Vo, Jo-Anne Baltos, Mariama Jaiteh, Andreas Luttens, Stefanie Kampen, Arthur Christopoulos, Jan Kihlberg, Lauren Therese May, Jens Carlsson
Summary: A structure-based virtual screening approach was used to design subtype-selective ligands for A1 and A2A adenosine receptors. The study identified a non-conserved subpocket in the binding sites that could be exploited to identify A1R selective ligands. Computational screening predicted 20 A1R selective ligands, with 7 of them exhibiting micromolar activities against A1R. Further optimization resulted in antagonists with nanomolar potency and up to 76-fold A1R-selectivity. This study demonstrates the potential of structure-based virtual screening in guiding the discovery and optimization of subtype-selective ligands, enabling the development of safer drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Wessel A. C. Burger, Vi Pham, Ziva Vuckovic, Alexander S. Powers, Jesse I. Mobbs, Yianni Laloudakis, Alisa Glukhova, Denise Wootten, Andrew B. Tobin, Patrick M. Sexton, Steven M. Paul, Christian C. Felder, Radostin Danev, Ron O. Dror, Arthur Christopoulos, Celine Valant, David M. Thal
Summary: The M4 muscarinic acetylcholine receptor is a significant drug target for the treatment of psychosis, cognition, and addiction. The clinical trial of xanomeline has shown promise in improving symptoms and the cryo-EM structure reveals the binding mechanism, providing insight into its complex pharmacology.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Ping Luo, Wenbo Feng, Shanshan Ma, Antao Dai, Kai Wu, Xianyue Chen, Qingning Yuan, Xiaoqing Cai, Dehua Yang, Ming-Wei Wang, H. Eric Xu, Yi Jiang
Summary: G protein-coupled receptors (GPCRs) are regulated by accessory proteins such as melanocortin receptor accessory protein 1 (MRAP1), which plays a crucial role in the regulation of melanocortin receptor 2 (MC2R). The activation of MC2R by adrenocorticotropic hormone (ACTH) and its involvement in glucocorticoid biogenesis have significant effects on the hypothalamic-pituitary-adrenal axis and related disorders. This study presents the cryo-electron microscopy structure of the ACTH-bound MC2R-G(s)-MRAP1 complex, revealing the unique structure and stabilizing effect of MRAP1 on ACTH binding and MC2R activation. The findings provide insights into GPCR regulation and the design of therapeutic agents targeting MC2R.
Meeting Abstract
Pharmacology & Pharmacy
Celine Valant, Alexander Powers, Vi Pham, Wessel Burger, Emma van der Westhuizen, Nicholas Barnes, Steven Paul, Arthur Christopoulos, David Thal, Christian Felder, Ron Dror
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Meeting Abstract
Pharmacology & Pharmacy
Huong Thi Mai Nguyen, Emma van der Westhuizen, Elham Khajehali, Arthur Christopoulos, Celine Valant
BRITISH JOURNAL OF PHARMACOLOGY
(2023)