Article
Medicine, Research & Experimental
Helen E. Burston, Oliver A. Kent, Laudine Communal, Molly L. Udaskin, Ren X. Sun, Kevin R. Brown, Euihye Jung, Kyle E. Francis, Jose La Rose, Joshua Lowitz, Ronny Drapkin, Anne-Marie Mes-Masson, Robert Rottapel
Summary: Relaxin and its associated GPCR RXFP1 form an autocrine signaling loop essential for ovarian cancer in vivo tumorigenesis, cell proliferation, and viability. Relaxin signaling activates expression of prooncogenic pathways, and inflammatory cytokines can activate Relaxin transcription.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Pharmacology & Pharmacy
David Speck, Gunnar Kleinau, Mark Meininghaus, Antje Erbe, Alexandra Einfeldt, Michal Szczepek, Patrick Scheerer, Vera Puetter
Summary: G-protein coupled receptors (GPCR) play a crucial role in transducing extracellular stimuli into cells, making them an important target in medical and pharmacological research. However, the expression and purification of these receptors have remained challenging due to their specificities and the need for appropriate experimental conditions. In this study, the expression and purification of a specific GPCR (RXFP1) were described, and various constructs were designed for functional and structural studies. The results may support further research on RXFP1 receptors, such as small molecule ligand screening or structural elucidation.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Cell Biology
Conor Hennessy, Declan P. McKernan
Summary: PRRs play a central role in inflammation following microbial infection by recognizing molecular patterns, and targeting them may offer a potential therapeutic approach for chronic inflammatory diseases and infections.
Review
Biochemistry & Molecular Biology
Hanne Leysen, Deborah Walter, Lore Clauwaert, Lieselot Hellemans, Jaana van Gastel, Lakshmi Vasudevan, Bronwen Martin, Stuart Maudsley
Summary: During aging, the body becomes less capable of dealing with cellular stress and repairing damage, leading to impaired functionality and increased mortality risk. Combining interventions that support glucose metabolism and protect/repair DNA damage has been shown to be an effective anti-aging strategy. The ARF GTPase activating protein GIT2 plays a key role in the aging process by controlling both DNA repair and glucose metabolism. The relaxin-3 receptor RXFP3 forms a close relationship with GIT2 and is directly affected by DNA damage and oxidative stress. Stimulating the RXFP3/RLN3 signaling pathway can regulate the DNA damage response and repair processes, providing a significant impact on aging and age-related disorders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Chemistry, Medicinal
Xinjie Song, Nikhil Kirtipal, Sunjae Lee, Petr Maly, Shiv Bharadwaj
Summary: Caffeine acts as a nonselective adenosine receptor antagonist and has both beneficial effects and paradoxical effects on human health. This article provides an overview of caffeine's validated targets and its impact on organ-specific physiology and pathophysiology. Further studies are needed to explore caffeine-induced changes in specific conditions for therapeutic applications.
PHYTOTHERAPY RESEARCH
(2023)
Review
Biochemistry & Molecular Biology
Wei Wang, Xiangjun Wang, Feng Yao, Chao Huang
Summary: The lysyl oxidase (LOX) family plays a crucial role in tumor microenvironment remodeling and is closely associated with tumor invasion, metastasis, and immunomodulation. The family may serve as an effective target for tumor therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Editorial Material
Immunology
Andre G. Buret, Thibault Allain
Summary: Gut microbiota consist of viruses, bacteria, fungi, and Eukarya, and form biofilms. In a healthy state, these biofilms attach to the intestinal mucus surface without contacting the epithelium. Imbalances between these biofilms and the host can lead to invasive pathobionts from commensal communities and contribute to disease. Environmental factors have a greater influence than genetics on the shifts in microbiota populations and function, even between low-income and industrialized countries. These findings have significant implications for the development of novel therapies targeting microbiota dysbiosis.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Review
Pharmacology & Pharmacy
Kate F. Byrne, Ajay Pal, James F. Curtin, John C. Stephens, Gemma K. Kinsella
Summary: The focus of the review is on G-protein-coupled receptor (GPCR) targets, with chemokine, cannabinoid, and dopamine receptors showing promise. Further research is needed on potential targets such as MC4R, adhesion receptors, LPA, and Smo receptors to develop new drug-screening strategies for safe and effective GBM therapies.
DRUG DISCOVERY TODAY
(2021)
Review
Pathology
Sun-Ji Park, Chuang Li, Ying Maggie Chen
Summary: Maintaining Ca2+ homeostasis is crucial for cellular function and survival, with the endoplasmic reticulum acting as the major intracellular Ca2+ store. Dysregulation of ER Ca2+ homeostasis is associated with various diseases, particularly in kidney diseases, highlighting the importance of ER Ca2+ channels, pumps, and binding proteins. Despite advancements in understanding, treatment for ER Ca2+ imbalance in kidney diseases remains elusive.
AMERICAN JOURNAL OF PATHOLOGY
(2021)
Review
Medicine, Research & Experimental
Xilu Wang, Yingying Zhou, Dali Wang, Yi Wang, Zhaoyu Zhou, Xiulan Ma, Xiaofang Liu, Yaodong Dong
Summary: Administration of cisplatin, a common chemotherapeutic drug, can lead to hearing loss. This is caused by injury to the stria vascularis, degeneration of the spiral ganglion, and death of hair cells. Cisplatin disrupts organelle metabolism, induces oxidative stress, and targets DNA to cause damage in hair cells. Inflammation also plays a role in cisplatin-induced ototoxicity.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Review
Biochemistry & Molecular Biology
Laura Necula, Lilia Matei, Denisa Dragu, Ioana Pitica, Ana Neagu, Coralia Bleotu, Carmen C. Diaconu, Mihaela Chivu-Economescu
Summary: This article provides an overview of the application of the collagen family as biomarkers in cancer therapy, and discusses their role in promoting tumor growth and creating a permissive environment for metastatic dissemination.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Ansoo Lee, Hyunah Choo, Byungsun Jeon
Summary: Autism spectrum disorder is a group of neurodevelopmental disorders characterized by repetitive behaviors and difficulties with social interaction and communication. Existing drugs can alleviate some symptoms, but not the core symptoms. Serotonin receptors have emerged as potential therapeutic targets for ASD treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Oncology
Peng Ye, Yiran Wang, Ruiqi Li, Wanlu Chen, Lu Wan, Peiling Cai
Summary: This review discusses the discovery, functions, and roles of HER family members in cancer, and focuses on the development and recent updates of therapies targeting HER family members, with a particular emphasis on colorectal cancer.
CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
(2022)
Article
Pharmacology & Pharmacy
Stephanie A. Heusser, Stephan A. Pless
Summary: ASICs, as potential pharmaceutical targets, may have therapeutic potential in disorders such as ischemic stroke, pain, anxiety, and cardiac pathologies, but face challenges in pharmacological targeting.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2021)
Article
Immunology
Koichi Yuki, Sophia Koutsogiannaki
Summary: Understanding host immunological responses is crucial in developing appropriate therapeutic approaches for different types of sepsis. Pattern recognition receptors play a key role in bacterial, fungal, and viral sepsis, and have therapeutic potential.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Adam L. Valkovic, Martina Kocan, Brad Hoare, Sarah Marshall, Daniel J. Scott, Ross A. D. Bathgate
Summary: This article introduces a new BRET-based cGMP sensor called CYGYEL, which enables efficient and rapid detection of cGMP activity in plate-based assays and successfully detects cGMP signals in different cell types.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Jon Merlin, Julia Park, Teresa H. Vandekolk, Stewart A. Fabb, Jeanne Allinne, Roger J. Summers, Christopher J. Langmead, Darren M. Riddy
Summary: This study comprehensively shows how several natural mediators and synthetic ligands signal through three specialized proresolving mediator GPCRs using multiple ligands from different classes across four-six endpoint signaling assays. The potential of these receptors in treating specific autoimmune diseases, including rheumatoid arthritis, systemic scleroderma, and systemic lupus erythennatosus, is highlighted.
MOLECULAR PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Annunziata D'Ercole, Silvia Nistri, Lorenzo Pacini, Alfonso Carotenuto, Federica Santoro, Anna Maria Papini, Ross A. D. Bathgate, Daniele Bani, Paolo Rovero
Summary: This study synthesized and tested a set of low molecular weight peptides in order to obtain RLX analogues with improved pharmacokinetic features. However, none of these peptides showed sufficient affinity to the specific RLX receptor RXFP1 or RLX-like biological effects.
FRONTIERS IN PHARMACOLOGY
(2022)
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)
Article
Cell Biology
Fabian Bumbak, Miquel Pons, Asuka Inoue, Juan Carlos Paniagua, Fei Yan, Hongwei Wu, Scott A. Robson, Ross A. D. Bathgate, Daniel J. Scott, Paul R. Gooley, Joshua J. Ziarek
Summary: Nuclear magnetic resonance (NMR) studies have shown that fast methyl sidechain dynamics can provide information about entropically-driven allostery. This study focuses on the fast dynamics of a thermostabilized G protein-coupled receptor (GPCR), neurotensin receptor 1 (NTS1), using 13C epsilon-methionine chemical shift-based global order parameters. The results indicate the presence of substates with different lifetimes in the NTS1 solution ensemble, and the rapid fluctuations of individual methionine residues are correlated with ligand pharmacology, suggesting a role for sub-microsecond dynamics and conformational entropy in GPCR ligand discrimination.
Article
Medicine, Research & Experimental
Fariha Alam, Tracey A. Gaspari, Barbara K. Kemp-Harper, Edward Low, Aaron Aw, Dorota Ferens, Iresha Spizzo, Ann-Maree Jefferis, Praveen Praveen, Robert E. Widdop, Ross A. D. Bathgate, Mohammed Akhter Hossain, Chrishan S. Samuel
Summary: This study found that B7-33 can retain the cardioprotective effects of RLX and has a better therapeutic effect compared to the ACE inhibitor perindopril. Therefore, B7-33 could be considered as a cost-effective cardioprotective therapy.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Review
Pharmacology & Pharmacy
Emma T. van der Westhuizen
Summary: Autism is a neurodevelopmental condition that varies in symptoms and severity among individuals. Genetic sequencing has identified mutations in autistic individuals, particularly in genes encoding G protein-coupled receptors (GPCRs), which are proteins that transmit messages from outside the cell to the inside. Mutations in GPCRs can disrupt their function and signaling in the brain. This review summarizes the current understanding of how single nucleotide variations in GPCRs impact their function and contribute to autism.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Pharmacology & Pharmacy
Anh T. N. Nguyen, Diep T. N. Nguyen, Huan Yee Koh, Jason Toskov, William MacLean, Andrew Xu, Daokun Zhang, Geoffrey I. Webb, Lauren T. May, Michelle L. Halls
Summary: The application of artificial intelligence in drug discovery for G protein-coupled receptors (GPCRs) is expanding rapidly. It can assist in understanding the actions of GPCRs, discovering new ligand-GPCR interactions, and predicting clinical responses. This article provides an overview of artificial intelligence concepts and its applications in different stages of GPCR drug discovery. The benefits and limitations of artificial intelligence are discussed, along with the potential for further development in assisting GPCR drug discovery.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Pharmacology & Pharmacy
Alastair C. Keen, Manuela Jorg, Michelle L. L. Halls
Summary: The ubiquitin-proteasome system is a major pathway for protein degradation in cells, and methods have been developed to exploit this system for targeted protein degradation. Targeted protein degraders have been useful tools in discovery research and are being developed as therapeutics. However, most targeted protein degrader technologies have been developed for cytosolic proteins, while examples for G protein-coupled receptor (GPCR) degradation are limited. This review discusses the strategies used for applying targeted protein degradation to GPCRs and explores alternative approaches used for degrading other integral membrane proteins.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Obstetrics & Gynecology
Ann-Kristin Dicke, Jakob Albrethsen, Bradley L. Hoare, Margot J. Wyrwoll, Alexander S. Busch, Daniela Fietz, Adrian Pilatz, Clara Buehlmann, Anders Juul, Sabine Kliesch, Joerg Gromoll, Ross A. D. Bathgate, Frank Tuettelmann, Birgit Stallmeyer
Summary: This study reveals that bi-allelic loss-of-function variants in the INSL3 and RXFP2 genes are associated with bilateral cryptorchidism and male infertility, while heterozygous variant carriers are unaffected phenotypically. These findings have diagnostic value for patients with familial/bilateral cryptorchidism and shed light on the importance of INSL3 and RXFP2 in testicular descent and fertility.
HUMAN REPRODUCTION
(2023)
Article
Biochemistry & Molecular Biology
Praveen Praveen, Chao Wang, Thomas N. G. Handley, Hongkang Wu, Chrishan S. S. Samuel, Ross A. D. Bathgate, Mohammed Akhter Hossain
Summary: Human relaxin-2 (H2 relaxin) has therapeutic importance due to its anti-fibrotic, vasodilatory, and cardioprotective effects. Relaxin family peptide receptor 1 (RXFP1), the receptor for relaxin, is a potential target for treating fibrosis and related disorders. A single-chain agonist, B7-33 peptide, has been developed based on the B-chain of H2 relaxin but has a short circulation time in vitro.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Shubo Jin, Erin. J. J. Campbell, Chi Kin Ip, Sharon Layfield, Ross A. D. Bathgate, Herbert Herzog, Andrew. J. J. Lawrence
Summary: The nucleus accumbens shell is an important part of the reward circuit, responsible for encoding reward-associated environments. This study identified the ventral subiculum as the brain region with the highest glutamatergic input to the shell. By analyzing the molecular characteristics of different glutamatergic projections from the ventral subiculum to the nucleus accumbens shell, the study revealed differential gene enrichment and highlighted potential differences in neuronal projections.
NEUROCHEMICAL RESEARCH
(2023)
Article
Chemistry, Medicinal
Mohammed Akhter Hossain, Praveen Praveen, Nurhayati Ahmad Noorzi, Hongkang Wu, Ian P. Harrison, Thomas Handley, Stavros Selemidis, Chrishan S. Samuel, Ross A. D. Bathgate
Summary: H2 relaxin is a peptide hormone that acts through the RXFP1 receptor and has important biological functions. Overexpression of H2 relaxin and RXFP1 in prostate cancer suggests their potential as targets for inhibiting tumor growth. In this study, a novel high-affinity RXFP1 antagonist, H2 B-R13HR, was developed and shown to inhibit relaxin-mediated tumor growth in a mouse model. This compound provides insights into relaxin actions through RXFP1 and may have therapeutic potential for prostate cancer.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Chemistry, Medicinal
Manuela Jorg, Emma T. van der Westhuizen, Yao Lu, K. H. Christopher Choy, David M. Shackleford, Elham Khajehali, Andrew B. Tobin, David M. Thal, Ben Capuano, Arthur Christopoulos, Celine Valant, Peter J. Scammells
Summary: The synthesis and comprehensive pharmacological evaluation of M4 mAChR PAMs structurally related to 1e, Me-C-c, [11C]MK-6884 and [18F]12 were reported. Small structural changes to the PAMs resulted in significant differences in baseline, potency, and maximum effect measures in cAMP assays compared to the endogenous ligand acetylcholine (ACh). The discovery of novel PAMs with improved allosteric properties, 6k and 6l, and their ability to cross the blood-brain barrier make them more suitable for future preclinical assessment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Thomas N. G. Handley, Praveen Praveen, Julien Tailhades, Hongkang Wu, Ross A. D. Bathgate, Mohammed Akhter Hossain
Summary: H2 relaxin is a peptide hormone with vasodilatory and anti-fibrotic effects. Researchers have developed B7-33, a derived peptide from H2 relaxin, which showed equivalent potency and anti-fibrotic effects in fibroblasts. B7-33 also reversed organ fibrosis in pre-clinical animal studies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Karlie R. Sharma, Christine M. Colvis, Griffih P. Rodgers, Douglas M. Sheeley
Summary: There are many genes within the druggable genome that have not been studied, and the US National Institutes of Health's program provides resources to explore these genes, with the potential for rapid impact on human health.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Mohammad Sameer Khan, B. H. Jaswanth Gowda, Waleed H. Almalki, Tanuja Singh, Amirhossein Sahebkar, Prashant Kesharwani
Summary: Mitochondria-specific functional liposomes hold great potential for cancer therapy. This review discusses the association between mitochondria and tumor formation, as well as the advantages of liposomes in delivering drugs to mitochondria.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Choong Yong Ung, Cristina Correia, Hu Li, Christopher M. Adams, Jennifer J. Westendorf, Shizhen Zhu
Summary: With increasing human life expectancy, the global medical burden of chronic diseases is growing. Chronic diseases often involve malfunctioning of multiple organs, and understanding the interorgan crosstalk is crucial to understanding the etiology of chronic diseases. Researchers have proposed the locked-state model (LoSM) and cutting-edge systems biology and artificial intelligence strategies to decipher chronic multiorgan locked states. The findings have important clinical implications for improving treatments for chronic diseases.
DRUG DISCOVERY TODAY
(2024)
