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Lysophosphatidic acids (LPAs) are bioactive phospholipids implicated in a wide range of cellular activities that regulate a diverse array of biological functions. They recognize two types of G protein-coupled receptors (LPARs): LPA1-3 receptors and LPA4-6 receptors that belong to the endothelial gene (EDG) family and non-endothelial gene family, respectively. In recent years, the LPA signaling pathway has captured an increasing amount of attention because of its involvement in various diseases, such as idiopathic pulmonary fibrosis, cancers, cardiovascular diseases and neuropathic pain, making it a promising target for drug development. While no drugs targeting LPARs have been approved by the FDA thus far, at least three antagonists have entered phase Ⅱ clinical trials for idiopathic pulmonary fibrosis (BMS-986020 and BMS-986278) and systemic sclerosis (SAR100842), and one radioligand (BMT-136088/18F-BMS-986327) has entered phase Ⅰ clinical trials for positron emission tomography (PET) imaging of idiopathic pulmonary fibrosis. This article provides an extensive review on the current status of ligand development targeting LPA receptors to modulate LPA signaling and their therapeutic potential in various diseases. Read full article

Coordinated transcriptomics and peptidomics of central nervous system identify neuropeptides and their G protein-coupled receptors in the oriental fruit moth Grapholita molesta The oriental fruit moth Grapholita molesta is a cosmopolitan pest of orchard, which causes serious economic losses to the fruit production. Neuropeptides and their specific receptors (primarily G protein-coupled receptors, GPCRs) regulate multiple biological functions in insects and represent promising next-generation pest management strategy. Here, we generated a transcriptome of the central nervous system (CNS) of G. molesta. Overall, 57 neuropeptide precursor genes were identified and 128 various mature peptides were predicted from these precursors. Using peptidomic analysis of CNS of G. molesta, we identified total of 28 mature peptides and precursor-related peptides from 16 precursors. A total of 41 neuropeptide GPCR genes belonging to three classes were also identified. These GPCRs and their probable ligands were predicted. Additionally, expression patterns of these 98 genes in various larval tissues were evaluated using quantitative real-time PCR. Taken together, these results will benefit further investigations to determine physiological functions and pharmacological characterization of neuropeptides and their GPCRs in G. molesta; and to develop specific neuropeptide-based agents for this tortricid fruit pest control. Read full article

Odorant G protein-coupled receptors as potential therapeutic targets for adult diffuse gliomas: a systematic analysis and review Odorant receptors (ORs) account for about 60% of all human G protein-coupled receptors (GPCRs). OR expression outside of the nose has functions distinct from odor perception, and may contribute to the pathogenesis of disorders including brain diseases and cancers. Glioma is the most common adult malignant brain tumor and requires novel therapeutic strategies to improve clinical outcomes. Here, we outlined the expression of brain ORs and investigated OR expression levels in glioma. Although most ORs were not ubiquitously expressed in gliomas, a subset of ORs displayed glioma subtype-specific expression. Moreover, through systematic survival analysis on OR genes, OR51E1 (mouse Olfr558) was identified as a potential biomarker of unfavorable overall survival, and OR2C1 (mouse Olfr15) was identified as a potential biomarker of favorable overall survival in isocitrate dehydrogenase (IDH) wild-type glioma. In addition to transcriptomic analysis, mutational profiles revealed that somatic mutations in OR genes were detected in ＞ 60% of glioma samples. OR5D18 (mouse Olfr1155) was the most frequently mutated OR gene, and OR5AR1 (mouse Olfr1019) showed IDH wild-type-specific mutation. Based on this systematic analysis and review of the genomic and transcriptomic profiles of ORs in glioma, we suggest that ORs are potential biomarkers and therapeutic targets for glioma. [BMB Reports 2021; 54(12): 601-607]. Read full article

Open source programming packages for cheminformatics and structural bioinformatics are powerful tools to build modular, reproducible, and reusable pipelines for computer-aided drug design (CADD). While documentation for such tools is available, only few freely accessible examples teach underlying concepts focused on CADD applications, addressing especially users new to the field. TeachOpenCADD is a teaching platform developed by students for students, which provides teaching material for central CADD topics. Since we cover both the theoretical as well as practical aspect of these topics, the platform addresses students and researchers with a biological/chemical as well as a computational background. For each topic, an interactive Jupyter Notebook is offered, using open source packages such as the Python packages rdkit, pypdb, biopandas, nglview, and mdanalysis. Topics are continuously expanded and open for contributions from the community. Beyond their teaching purpose, the TeachOpenCADD material can serve as starting point for users’ project-directed modifications and extensions. Details

Nocturnal asthma is characterized by heightened bronchial reactivity at night, and plasma melatonin concentrations are higher in patients with nocturnal asthma symptoms. Numerous physiological effects of melatonin are mediated via its specific G protein-coupled receptors (GPCRs) named the MT1 receptor, which couples to both Gq and Gi proteins, and the MT2 receptor, which couples to Gi. We investigated whether melatonin receptors are expressed on airway smooth muscle; whether they regulate intracellular cyclic AMP (cAMP) and calcium concentrations ([Ca2+]i), which modulate airway smooth muscle tone; and whether they promote airway smooth muscle cell proliferation. We detected the mRNA and protein expression of the melatonin MT2 but not the MT1 receptor in native human and guinea pig airway smooth muscle and cultured human airway smooth muscle (HASM) cells by RT-PCR, immunoblotting, and immunohistochemistry. Activation of melatonin MT2 receptors with either pharmacological concentrations of melatonin (10-100 µM) or the nonselective MT1/MT2 agonist ramelteon (10 µM) significantly inhibited forskolin-stimulated cAMP accumulation in HASM cells, which was reversed by the Gαi protein inhibitor pertussis toxin or knockdown of the MT2 receptor by its specific siRNA. Although melatonin by itself did not induce an initial [Ca2+]i increase and airway contraction, melatonin significantly potentiated acetylcholine-stimulated [Ca2+]i increases, stress fiber formation through the MT2 receptor in HASM cells, and attenuated the relaxant effect of isoproterenol in guinea pig trachea. These findings suggest that the melatonin MT2 receptor is expressed in ASM, and modulates airway smooth muscle tone via reduced cAMP production and increased [Ca2+]i. Read full article

G protein-coupled receptor kinase 2 is essential to enable vasoconstrictor-mediated arterial smooth muscle proliferation Hypertension is associated with increased production and circulation of vasoconstrictors, resulting in enhanced signalling through their cognate G protein-coupled receptors (GPCR). Prolonged vasoconstrictor GPCR signalling increases arterial contraction and stimulates signalling pathways that promote vascular smooth muscle cell (VSMC) proliferation, contributing to the development of atherosclerotic plaques, re-stenosis lesions and vascular remodelling. GPCR signalling through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) promotes VSMC proliferation. In VSMC, G protein-coupled receptor kinase 2 (GRK2) is known to regulate numerous vasoconstrictor GPCRs and their downstream signalling pathways. As GRK2 is implicated in controlling various aspects of cellular growth, we examined whether GRK2 could affect VSMC proliferation. Using two indices of cell growth, we show that PI3K inhibition and depletion of GRK2 expression produced a similar ablation of pro-proliferative vasoconstrictor-stimulated VSMC growth. Furthermore, GRK2-knockdown ablated the sustained phase of endothelin-1 and angiotensin-II-stimulated Akt phosphorylation, whilst the peak (5 min) phase was unaffected. Conversely, the GRK2 inhibitor compound 101 did not affect vasoconstrictor-driven Akt phosphorylation. Vasoconstrictor-stimulated phosphorylation of the Akt substrates GSK3α and GSK3β was ablated following RNAi-mediated GRK2 depletion, or after PI3K inhibition. Moreover, GRK2 knockdown prevented endothelin-1 and angiotensin-II from increasing cyclin D1 expression. These data suggest GRK2 expression is essential to facilitate vasoconstrictor-driven VSMC proliferation through its ability to promote efficient prolonged PI3K-Akt signalling, and thus relieve the GSK3-mediated block on cell cycling. Considering VSMC GRK2 expression increases early in the development of hypertension, this highlights the potential for GRK2 to promote VSMC growth and exacerbate hypertensive pathophysiological vascular remodelling. Read full article

December 2021 Perkins’ Head of Molecular Endocrinology and Pharmacology, Professor Kevin Pfleger, was appointed President of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) earlier this month. Coincidentally, on the same day, Prof Pfleger was announced as a Fellow of the British Pharmacological Society. "ASCEPT is the peak professional society devoted to advancing excellence in Clinical and Experimental Pharmacology and Toxicology in Australia and New Zealand. Established in 1966, ASCEPT is affiliated with the International Union of Basic and Clinical Pharmacology (IUPHAR) and the International Union of Toxicology (IUTOX). Prof Pfleger has served on the ASCEPT Board since 2016 and was Chair of the Scientific Advisory Committee in 2017 and 2018. “I am honoured to be appointed President of ASCEPT, and am particularly excited given the Society’s conference will be held in Perth next year, in collaboration with the Australasian Pharmaceutical Science Association (APSA).”" Read more at the source #DrGPCR #GPCR #IndustryNews

December 2021 "30/11/2021 Confo will work together with Regeneron to apply its GPCR drug discovery platform to enable functional antibody discovery. VIB spin-off Confo Therapeutics today announced that it has entered into a collaborative agreement with Regeneron Pharmaceuticals, Inc. whereby Confo’s technology platform, which uses conformationally selective VHH antibodies – ConfoBodies® – to stabilize GPCRs (G protein-coupled receptors) in disease-relevant conformations, will be applied with the goal of enabling the discovery of novel therapeutic antibody drug candidates. " Read more at the source #DrGPCR #GPCR #IndustryNews

December 2021 Crinetics Pharmaceuticals announced the formation of an independently operated new company, Radionetics Oncology. Radionetics aims to develop a deep pipeline of novel, targeted, nonpeptide radiopharmaceuticals for the treatment of a broad range of oncology indications "– Co-founded by Crinetics, 5AM Ventures and Frazier Healthcare Partners, the New Company Launches with $30M in Initial Financing Provided by 5AM and Frazier – Pipeline is Built from Crinetics’ Core Nonpeptide Platform and Includes Drug Candidates and Leads Against 10 Oncology Targets – Radionetics and Crinetics to Collaborate on Multiple Additional targets SAN DIEGO, October 18, 2021 — Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors, together with 5AM Ventures and Frazier Healthcare Partners, today announced the formation of an independently operated new company, Radionetics Oncology. Radionetics aims to develop a deep pipeline of novel, targeted, nonpeptide radiopharmaceuticals for the treatment of a broad range of oncology indications." Read more at the source #DrGPCR #GPCR #IndustryNews

December 2021 "Ottawa, Ontario, Canada, Nov. 30, 2021 -- Orion Biotechnology, a clinical stage company unlocking the therapeutic potential of G Protein-Coupled Receptors (GPCRs) with a novel drug modality, proven discovery platform and best-in-class molecules, today announced the successful completion of its OB-004 lead optimization. OB-004 is a GPCR targeted protein analog of CCL2 that targets the CCR2 receptor. The CCL2/CCR2 pathway plays an important role in oncology, inflammatory, metabolic, and neurological disorders." Read more at the source #DrGPCR #GPCR #IndustryNews

December 2021 "Early-stage studies of COVID-19 treatments from the likes of Vir Biotechnology Inc. and Trevena Inc. could offer potential new weapons against omicron and future viral variants. The omicron strain of the virus was first identified in South Africa in early November, and an existing treatment has already shown positive results in the lab. While vaccine-makers race to test their shots against the variant, the monoclonal antibody sotrovimab from Vir and partner GlaxoSmithKline PLC posted results Dec. 7 demonstrating activity against the omicron spike protein. Sotrovimab is the first monoclonal antibody showing preclinical efficacy against all COVID-19 variants, including the delta and omicron mutations, Vir CEO George Scangos said on a Dec. 7 call with analysts." Read more at the source #DrGPCR #GPCR #IndustryNews

December 2021 OMass Therapeutics's founder, Carol Robinson, has been awarded the prestigious Louis-Jeantet Prize for Medicine 2022 by the Louis-Jeantet Foundation and the 2022 Benjamin Franklin Medal in Chemistry from The Franklin Institute "Huge congratulations to our founder, Carol Robinson, who has been awarded the prestigious Louis-Jeantet Prize for Medicine 2022 by the Louis-Jeantet Foundation and the 2022 Benjamin Franklin Medal in Chemistry from The Franklin Institute yesterday for contributions to the field of mass spectrometry and establishing it as method to analyse proteins in their native state. Her work in the field has been instrumental and is set to shape the future of drug discovery for years to come. #DrugDiscovery #MassSpec #Award #massspectrometry" Read more at the source #DrGPCR #GPCR #IndustryNews

December 2022 Sosei Heptares Enters Antibody Discovery Agreement with Twist Bioscience to Discover and Develop Novel Therapeutic Antibodies against GPCR Targets "Collaboration aims to combine Twist’s proprietary synthetic antibody libraries and sophisticated bioinformatics expertise with Sosei Heptares’ world-leading StaR® (stabilized receptor) platform to generate novel antibody leads to disease-relevant GPCR targets Tokyo, Japan and Cambridge, UK, 16 December 2021 – Sosei Group Corporation (“the Company”; TSE: 4565), the world leader in GPCR-focused structure-based drug design (SBDD) and development, and Twist Bioscience Corporation (Nasdaq: TWST), a company enabling customers to succeed through its offering of high-quality synthetic DNA using its silicon platform, announced a strategic collaboration to discover therapeutic antibodies against G protein-coupled receptors (GPCR) identified by Sosei Heptares." Read more at the source #DrGPCR #GPCR #IndustryNews

Excited to hear Dr. Sandra Berndt talk about new structural perspectives in GPCR-mediated Src family kinase activation. Register here (FREE) https://www.ecosystem.drgpcr.com/dr-gpcr-virtual-cafe #drgpcr #gpcr #virtualcafe

Ep 57 of the Dr. GPCR podcast is now available! Our guest is Dr. Peter Banks, Scientific Director at BioTek Instruments! Learn about his career today! Listen where you get your podcasts. https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/ #gpcr #drgpcr #podcast

Episode 56 of the Dr. GPCR podcast is now available! Our guest is Dr. Adriano Marchese! Learn about his remarkable career and research in #GPCR signaling and trafficking. Listen where you get your podcasts https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/ #drgpcr #gpcr #podcast

Excited to hear Dr. Joe Clayton from BioTek Instruments talk about automated micro-plate-based methods for quantifying #GPCR activation. https://www.ecosystem.drgpcr.com/dr-gpcr-virtual-cafe/ #drgpcr #gpcr #virtualcafe

Episode 54 of the Dr. GPCR podcast is now available! Our guest is Dr. JoAnn Trejo! Sharing how she became a scientist, educator, mentor, and the powerhouse we know today. Listen where you get your podcasts https://www.ecosystem.drgpcr.com/dr-gpcr-podcast #gpcr #drgpcr #podcast

Genome-wide identification of 216 G protein-coupled receptor (GPCR) genes from the marine water flea Diaphanosoma celebensis G protein-coupled receptors (GPCRs) are considered to have originated from early evolution of eukaryotic species, therefore, the genome-wide identification of GPCR genes can provide insight into the adaptive strategy and evolutionary tendency in an animal taxon. Here, we identified a total 216 full-length GPCR genes in the marine water flea Diaphanosoma celebensis genome, which were classified into five distinct classes (A, B, C, F, and other). Phylogenetic comparison of GPCRs in D. celebensis to those in humans (Homo sapiens), fruitfly (Drosophila melanogaster), and freshwater water flea (Daphnia magna) reveals a high level of orthological relationship of amine, neuropeptide, and opsin receptor repertoire, while purinergic and chemokine receptors were highly differentiated in humans. Our findings suggest sporadic evolutionary processes within the GPCR gene families identified in D. celebensis. In this study, these results may provide a better understanding on the evolution of GPCRs, and expand our knowledge of the cladoceran GPCR gene repertories which in part, mediate cell physiological mechanisms in response to various environmental stimuli.

November 2021 "Nov. 15, 2021 LONDON – There’s not yet proof of the pudding, but Omass Therapeutics Ltd.’s new structure-based technology has passed a key test, in enabling the discovery of orally available small molecules aimed at intractable and poorly drugged membrane and complex-bound protein targets. The targets, including G protein-coupled receptors (GPCRs), intracellular protein complexes and solute carriers, are relevant to immunology indications and rare diseases with high unmet need." Read more at the source #DrGPCR #GPCR #IndustryNews

November 2021 Dr. Kevin Pfleger and Dr. Elizabeth Johnstone were awarded one of the 2022 Diabetes Research Grants at the World Diabetes Day Breakfast! "Congratulations to Perkins Professor Kevin Pfleger and Dr Elizabeth Johnstone who were awarded one of the 2022 Diabetes Research Grants at yesterday's annual World Diabetes Day Breakfast! This $60,000 grant from Diabetes Research WA will assist the Perkins' Molecular Endocrinology and Pharmacology Laboratory team who are investigating new ways to tackle the disease-inducing chronic inflammation that is linked to type 2 diabetes." Read more at the source #DrGPCR #GPCR #IndustryNews

November 2021 "So proud and grateful to receive honorary doctorate yesterday from Karolinska Institute and celebrate with my family in Stockholm." Read more at the source #DrGPCR #GPCR #IndustryNews

November 2021 Addex's strategic partner The Janssen Pharmaceutical Companies of Johnson & Johnson, Inc. has completed Phase 1 studies in Japan with JNJ-40411813 (ADX71149) "Geneva, Switzerland, November 15, 2021 – Addex Therapeutics (SIX: ADXN and Nasdaq: ADXN), a clinical-stage pharmaceutical company pioneering allosteric modulation-based drug discovery and development, today announced that Janssen Pharmaceuticals, Inc., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, has successfully completed Phase 1 studies in Japan with JNJ-40411813 (ADX71149). ADX71149 is a selective metabotropic glutamate type 2 (mGlu2) receptor positive allosteric modulator (PAM). The successful completion of this Phase 1 safety program will enable centers in Japan to be included in a potential global development of ADX71149 for the treatment of epilepsy. " Read more at the source #DrGPCR #GPCR #IndustryNews

November 2021 Twist Bioscience Launches Revelar Biotherapeutics to Develop and Commercialize Novel COVID-19 and Other Antibody Therapeutics for Difficult to Treat Diseases "Nov 15, 2021 -- Executive Leadership Team Established with Demonstrated Success in Clinical, Regulatory and Commercial Development -- SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Nov. 15, 2021-- Twist Bioscience Corporation (NASDAQ: TWST), a company enabling customers to succeed through its offering of high-quality synthetic DNA using its silicon platform, today announced it has launched Revelar Biotherapeutics, Inc., an independently operated, new biotechnology company to develop and commercialize an antibody, discovered and optimized by Twist Biopharma, a division of Twist Bioscience, that neutralizes all known variants of concern of the SARS-CoV-2 virus in preclinical studies. In addition, Revelar will have the ability to leverage the antibody discovery and optimization platform of Twist Biopharma to license additional antibodies for up to five targets over the next four years."

November 2021 Positive Recommendation for Use of TAVNEOS™ (avacopan) in ANCA Vasculitis Adopted by European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) "SAN CARLOS, Calif., Nov. 12, 2021 (GLOBE NEWSWIRE) -- ChemoCentryx, Inc., (Nasdaq: CCXI), today announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending marketing authorization for the Company’s TAVNEOS (avacopan), an orally administered selective complement 5a receptor inhibitor, in combination with a rituximab or cyclophosphamide regimen, indicated for the treatment of adult patients with severe, active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)." Read more at the source #DrGPCR #GPCR #IndustryNews

November 2021 "November 11, 2021 7:00am EST Patricia Drake appointed new Chief Commercial Officer CHESTERBROOK, Pa., Nov. 11, 2021 -- Trevena, Inc. (Nasdaq: TRVN), a biopharmaceutical company focused on the development and commercialization of novel medicines for patients with central nervous system (CNS) disorders, today announced the addition of Patricia Drake to its senior leadership team as Chief Commercial Officer." Read more at the source #DrGPCR #GPCR #IndustryNews

November 2021 "Target class-specific libraries mean you need to screen less to identify high-quality antibodies. Aaron Sato, Chief Scientific Officer at Twist Bioscience, elaborates. Antibody developers are increasingly utilising antibody libraries to derive high-quality, drug-like biologics. However, only a few general-purpose libraries have been commercially available for drug discovery. As a result, most approved library-derived antibodies originate from just three libraries. The drugs also target relatively low-hanging fruit: like cytokines or tyrosine kinase receptors. To target hard-to-drug targets like G protein-coupled receptors (GPCRs), more libraries, including better and more targeted libraries, are needed." Read more at the source #DrGPCR #GPCR #IndustryNews

November 2021 "Chronic use of most opioids causes tolerance; the new compounds avoid this and other unwanted qualities. November 22, 2021 JUPITER, FL—Scientists at Scripps Research in Florida have created a collection of new pain-relieving compounds that, like morphine and other drugs, provide relief via activation of opioid receptors, but without inducing many dangerous and unwanted side-effects that have driven opioid-related overdose and deaths." Read more at the source #DrGPCR #GPCR #IndustryNews

November 2021 Read more at the source #DrGPCR #GPCR #IndustryNews

November 2021 "Cambridge’s Japanese-owned life sciences company Sosei Heptares has clinched a lucrative deal with California-based NASDAQ-quoted business Neurocrine Biosciences. The vision is to develop novel muscarinic receptor agonists for schizophrenia and other neuropsychiatric disorders. Neurocrine Biosciences anticipates initiating a Phase 2 study with the selective M4 agonist HTL-0016878 in schizophrenia in 2022 and Phase 1 studies for a dual M1/M4 and selective M1 agonist in 2023." Read more at the source #DrGPCR #GPCR #IndustryNews