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.
Review
Endocrinology & Metabolism
Siyuan Shen, Chang Zhao, Chao Wu, Suyue Sun, Ziyan Li, Wei Yan, Zhenhua Shao
Summary: GPCRs, as the largest family of transmembrane proteins, regulate various physiological processes. However, their complicated signal transduction pathways and difficulties in drug development have presented challenges. By identifying new ligands that bind to allosteric sites, safer drugs for treating various diseases can be designed.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Article
Virology
Cassandra M. Bonavita, Timothy M. White, Joseph Francis, Helen E. Farrell, Nicholas J. Davis-Poynter, Rhonda D. Cardin
Summary: Human cytomegalovirus (HCMV) is a widespread pathogen infecting a large portion of the population worldwide, causing lifelong latent infection and exacerbating cardiovascular diseases. Murine CMV (MCMV) has been shown to replicate cardiovascular dysfunction observed in HCMV-induced myocarditis. In this study, the role of viral G-protein-coupled receptor homologs (vGPCRs) US28 and M33 in promoting heart infection was examined. The results revealed that M33 plays a role in promoting cardiac dysfunction during acute infection, while US28 protein could complement the function of M33 in the heart. These findings suggest that vGPCRs may contribute to long-term cardiac damage and dysfunction.
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
Multidisciplinary Sciences
Naotaka Tsutsumi, Shoji Maeda, Qianhui Qu, Martin Vogele, Kevin M. Jude, Carl-Mikael Suomivuori, Ouliana Panova, Deepa Waghray, Hideaki E. Kato, Andrew Velasco, Ron O. Dror, Georgios Skiniotis, Brian K. Kobilka, K. Christopher Garcia
Summary: This study reports the cryo-electron microscopy structures of HCMV-encoded GPCRs US28 and US27 forming nonproductive and productive complexes with host G proteins, providing new insights into their functional mechanisms in viral pathogenesis.
Article
Multidisciplinary Sciences
Jia Duan, Dan-Dan Shen, Tingting Zhao, Shimeng Guo, Xinheng He, Wanchao Yin, Peiyu Xu, Yujie Ji, Li-Nan Chen, Jinyu Liu, Huibing Zhang, Qiufeng Liu, Yi Shi, Xi Cheng, Hualiang Jiang, H. Eric Xu, Yan Zhang, Xin Xie, Yi Jiang
Summary: This study provides a structural basis for the allosteric-like agonism and G protein selectivity of a neuropeptide GPCR, galanin receptor. The unique binding pose of galanin and the important role of intracellular loop 2 (ICL2) in determining the selective coupling of G(q) to GAL2R are uncovered. These findings offer insights into peptide ligand recognition and allosteric activation of galanin receptors and reveal a general structural element for G(q) coupling selectivity.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Karim Nagi, H. Ongun Onaran
Summary: GPCRs are the largest family of approved therapeutic targets, with ligands stimulating these receptors often causing undesired side effects. Biased agonism offers potential for improving therapeutic responses, but the identification and quantification of biased agonists remain challenging.
CELLULAR SIGNALLING
(2021)
Review
Biochemistry & Molecular Biology
Raudah Lazim, Donghyuk Suh, Jai Woo Lee, Thi Ngoc Lan Vu, Sanghee Yoon, Sun Choi
Summary: The presence of GPCR dimers has sparked research into their importance in disease pathogenesis and drug design, uncovering new signaling pathways and potential therapeutic targets. The increasing influence of computational methods in research is providing new avenues for understanding the functions and interactions of GPCRs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Prashant Donthamsetti, David B. Konrad, Belinda Hetzler, Zhu Fu, Dirk Trauner, Ehud Y. Isacoff
Summary: G protein-coupled receptors (GPCRs) are common drug discovery targets, but the complexity of in vivo receptor activation has hindered drug development. Photopharmacology offers the potential to control drug action using light. Recent advances include a photoswitchable allosteric agonist that selectively activates receptors.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Multidisciplinary Sciences
Lisa A. Stott, Cheryl A. Brighton, Jason Brown, Richard Mould, Kirstie A. Bennett, Robert Newman, Heather Currinn, Flavia Autore, Alicia P. Higueruelo, Benjamin G. Tehan, Cliona MacSweeney, Michael A. O'Brien, Steve P. Watson
Summary: This study reports the identification of cannabinoid ligands Cannabidiol and O-1918 as inverse agonists of the orphan receptor GPR52, detailed the pharmacology of GPR52 and modeling of the receptor interaction, and discovered a novel central nervous system pharmacology for the polypharmacological agent and marketed drug Cannabidiol.
Article
Pharmacology & Pharmacy
Daisuke Yasuda, Fumie Hamano, Kazuyuki Masuda, Marta Dahlstrom, Daiki Kobayashi, Nana Sato, Takao Hamakubo, Takao Shimizu, Satoshi Ishii
Summary: GPR82 is an active G protein-coupled receptor (GPCR) that can be inhibited by cationic lysophospholipids, including edelfosine, lysophosphatidylcholine, and lysophosphatidylethanolamine. The inhibition of GPR82 by these compounds leads to the activation of Gi protein and subsequently inhibits insulin-induced extracellular signal-regulated kinase signaling pathway and adipocyte lipolysis. These findings suggest that cationic lysophospholipids can act as inverse agonists for GPR82 and have the potential to exert lipolytic effects.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Pedro Renault, Jesus Giraldo
Summary: Computational tools have been used to estimate the druggability of allosteric sites in GPCRs, but predicting hydrophobic sites remains challenging. This study introduces a dynamics-based approach using experimental structures, normal mode analysis, and molecular dynamics simulations to identify allosteric sites in beta 2AR, GCGR, and M2 receptors, showing promising predictive value.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Pharmacology & Pharmacy
Alexander Kalinkovich, Gregory Livshits
Summary: Osteoporosis is caused by imbalanced bone remodeling, and current medications may have severe side effects. The proposal of using synthetic GPCR modulators to develop new anti-osteoporosis drugs presents a promising approach in this field.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Multidisciplinary Sciences
Janik B. Hedderich, Margherita Persechino, Katharina Becker, Franziska M. Heydenreich, Torben Gutermuth, Michel Bouvier, Moritz Buenemann, Peter Kolb
Summary: Researchers computationally describe alternative allosteric pockets in G-protein-coupled receptors, identifying nine previously untargeted sites for synthetic ligands. They further investigate the potential of modulating receptor function through ligand binding to these sites.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Amanda E. Wakefield, David Bajusz, Dima Kozakov, Gyoergy M. Keseru, Sandor Vajda
Summary: Despite the limited number of GPCR structures cocrystallized with allosteric inhibitors, protein mapping has revealed the presence of druggable sites at the same locations in a large variety of GPCRs. These sites cluster at nine distinct locations and can be specifically targeted for allosteric modulation across GPCRs. The FTMap server facilitates protein mapping and is freely available for academic and governmental use.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Andrea Gross, Regine Brox, Dominik Damm, Nuska Tschammer, Barbara Schmidt, Jutta Eichler
BIOORGANIC & MEDICINAL CHEMISTRY
(2015)
Article
Cell Biology
Theresa Frank, Anna Reichel, Olav Larsen, Anne-Charlotte Stilp, Mette M. Rosenkilde, Thomas Stamminger, Takeaki Ozawa, Nuska Tschammer
CELL COMMUNICATION AND SIGNALING
(2016)
Article
Chemistry, Medicinal
Tizita Haimanot Admas, Viachaslau Bernat, Markus R. Heinrich, Nuska Tschammer
Article
Chemistry, Medicinal
Lampros Milanos, Regine Brox, Theresa Frank, Gasper Poklukar, Ralf Palmisano, Reiner Waibel, Juergen Einsiedel, Maximilian Duerr, Ivana Ivanovic-Burmazovic, Olav Larsen, Gertrud Malene Hjorto, Mette Marie Rosenkilde, Nuska Tschammer
JOURNAL OF MEDICINAL CHEMISTRY
(2016)
Article
Chemistry, Medicinal
Simone Thum, Artur K. Kokornaczyk, Tomoaki Seki, Monica De Maria, Natalia V. Ortiz Zacarias, Henk de Vries, Christina Weiss, Michael Koch, Dirk Schepmann, Masato Kitamura, Nuska Tschammer, Laura H. Heitman, Anna Junker, Bernhard Wuensch
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2017)
Article
Chemistry, Medicinal
Anja Kolaric, Urban Svajger, Tihomir Tomasic, Regine Brox, Theresa Frank, Nikola Minovski, Nuska Tschammer, Marko Anderluh
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Pharmacology & Pharmacy
Regine Brox, Lampros Milanos, Noureldin Saleh, Paul Baumeister, Armin Buschauer, Dagmar Hofmann, Markus R. Heinrich, Timothy Clark, Nuska Tschammerl
MOLECULAR PHARMACOLOGY
(2018)
Article
Multidisciplinary Sciences
Tanja Bartoschik, Stefanie Galinec, Christian Kleusch, Katarzyna Walkiewicz, Dennis Breitsprecher, Sebastian Weigert, Yves A. Muller, Changjiang You, Jacob Piehler, Thomas Vercruysse, Dirk Daelemans, Nuska Tschammer
SCIENTIFIC REPORTS
(2018)
Article
Chemistry, Multidisciplinary
Stefanie K. Fehler, Simone Maschauer, Sarah B. Hoefling, Amelie L. Bartuschat, Nuska Tschammer, Harald Huebner, Peter Gmeiner, Olaf Prante, Markus R. Heinrich
CHEMISTRY-A EUROPEAN JOURNAL
(2014)
Article
Chemistry, Medicinal
Ana Kralj, Elif Kurt, Nuska Tschammer, Markus R. Heinrich
Article
Multidisciplinary Sciences
Ralf C. Kling, Nuska Tschammer, Harald Lanig, Timothy Clark, Peter Gmeiner
Article
Multidisciplinary Sciences
Alina Tabor, Siegfried Weisenburger, Ashutosh Banerjee, Nirupam Purkayastha, Jonas M. Kaindl, Harald Huebner, Luxi Wei, Teja W. Groemer, Johannes Kornhuber, Nuska Tschammer, Nigel J. M. Birdsall, Gregory I. Mashanov, Vahid Sandoghdar, Peter Gmeiner
SCIENTIFIC REPORTS
(2016)
Article
Multidisciplinary Sciences
Pierre Calmet, Monica De Maria, Etienne Harte, Daniel Lamb, Maria Serrano-Vega, Ali Jazayeri, Nuska Tschammer, Isabel D. Alves
SCIENTIFIC REPORTS
(2016)
Article
Oncology
Namita Kundu, Xinrong Ma, Regine Brox, Xiaoxuan Fan, Tyler Kochel, Jocelyn Reader, Nuska Tschammer, Amy Fulton
BREAST CANCER-BASIC AND CLINICAL RESEARCH
(2019)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
