Jessica A I Muller, Lachlan A Bourke, Sam I D Campbell, Fernanda C Cardoso
{"title":"Venom peptides regulating Ca<sup>2+</sup> homeostasis: neuroprotective potential.","authors":"Jessica A I Muller, Lachlan A Bourke, Sam I D Campbell, Fernanda C Cardoso","doi":"10.1016/j.tips.2025.03.007","DOIUrl":"https://doi.org/10.1016/j.tips.2025.03.007","url":null,"abstract":"<p><p>Venom peptides specialized in modulating intracellular calcium ([Ca<sup>2+</sup>]<sub>i</sub>) offer a treasure trove of pharmacological properties to regulate aberrant Ca<sup>2+</sup> homeostasis in disease. Combined with emerging advances across peptide optimization, disease models, and functional bioassays, these venom peptides could unlock new therapies restoring Ca<sup>2+</sup> homeostasis. In this opinion, we explore the pharmacology of venom peptides modulating [Ca<sup>2+</sup>]<sub>i</sub> signaling along with recent breakthroughs propelling venom peptide-based drug discovery. We predict a transformative era in therapeutic development harnessing venom peptides targeting dysfunctional Ca<sup>2+</sup> signaling in intractable conditions such as neurodegenerative diseases.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":"46 5","pages":"407-421"},"PeriodicalIF":13.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Repurposing trifluoperazine for glioblastoma treatment.","authors":"Manam Inushi De Silva, Hui K Gan, Cedric Bardy","doi":"10.1016/j.tips.2025.03.005","DOIUrl":"https://doi.org/10.1016/j.tips.2025.03.005","url":null,"abstract":"<p><p>Glioblastoma (GBM) remains a therapeutic challenge due to its heterogeneity and plasticity, which drive treatment resistance, especially when compounded by interactions with the brain microenvironment. Recent preclinical evidence indicates that trifluoperazine (TFP) inhibits treatment-induced malignant reprogramming of tumour cells, potentially helping to reduce tumour plasticity. TFP targets calmodulin, dopamine receptors, and stress-responsive proteins (nuclear protein 1, NUPR1). Through these mechanisms, TFP has been shown to reduce tumour growth, sensitise tumours to chemoradiotherapy, and prolong survival in xenograft animal models. The clinical safety profile of TFP is well known from its use as an antipsychotic, and recent preclinical evidence further indicates that TFP has low toxicity to healthy neurons and glia despite transient functional effects on dopamine receptors. This Opinion explores TFP mechanisms of action and clinical activity to assess its suitability as a repurposed therapeutic option for GBM.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":"46 5","pages":"392-406"},"PeriodicalIF":13.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qingtong Zhou, Fenghui Zhao, Yao Zhang, Dehua Yang, Ming-Wei Wang
{"title":"Structural pharmacology and mechanisms of GLP-1R signaling.","authors":"Qingtong Zhou, Fenghui Zhao, Yao Zhang, Dehua Yang, Ming-Wei Wang","doi":"10.1016/j.tips.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.tips.2025.03.003","url":null,"abstract":"<p><p>Glucagon-like peptide-1 receptor (GLP-1R), a class B1 G protein-coupled receptor, plays critical roles in glucose homeostasis. Recent structural pharmacology studies using cryogenic electron microscopy, X-ray crystallography, mass spectrometry, and functional analyses, have provided valuable insights into its activation by endogenous hormones and mono- or dual agonists like semaglutide and tirzepatide, highly effective in treating type 2 diabetes and obesity. They highlight significant conformational changes in the extracellular and transmembrane domains of GLP-1R that drive receptor activation and downstream signal transduction. Additionally, allosteric modulators, supported by emerging structural information, show great promises as an alternative strategy. Future research investigating unexplored effector interactions, biased signaling, weight rebound mechanisms, and personalized therapy strategies will be critical for developing better therapeutic agents targeting GLP-1R.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":"46 5","pages":"422-436"},"PeriodicalIF":13.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"HSV-1 as a gene delivery platform for cancer gene therapy.","authors":"Yangkun Shen, Hucheng Zhang, Mengzhou Xue, Chunfu Zheng, Qi Chen","doi":"10.1016/j.tips.2025.02.006","DOIUrl":"10.1016/j.tips.2025.02.006","url":null,"abstract":"<p><p>Herpes simplex virus type 1 (HSV-1) is a DNA virus with strong replication capabilities, a large genomic payload (≥30 kb), and low toxicity, making it a prominent vector in cancer gene therapy. Clinically approved oncolytic HSV-1 (oHSV-1) variants, such as T-VEC and G47Δ, demonstrate safety and efficacy in localized tumors, but face challenges in treating metastatic disease. To address this issue, next-generation oHSV-1 designs focus on precision targeting and immune remodeling through the delivery of multiple exogenous genes. In this review, we provide an overview of the inherent characteristics of oHSV-1 as a gene delivery platform, focusing on its genetic modification strategies, safety challenges in clinical applications, and future directions to maximize its therapeutic potential.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"324-336"},"PeriodicalIF":13.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ribosome-directed cancer therapies: the tip of the iceberg?","authors":"Gregory C Howard, William P Tansey","doi":"10.1016/j.tips.2025.02.001","DOIUrl":"10.1016/j.tips.2025.02.001","url":null,"abstract":"<p><p>Ribosomes and ribosome biogenesis (RiBi) are universally corrupted in cancer, fueling the high rates of translation that sustain malignancy and creating opportunities for discriminating therapeutic intervention. Despite longstanding recognition of the promise of ribosome-directed cancer therapies, only a handful of such agents have been used in the clinic, and with limited success, and the true potential of this approach is unknown. In the past few years, however, understanding of cancer ribosome specialization and the intricacies of RiBi have advanced dramatically, opening opportunities that could not be imagined when existing agents were discovered. Here, we discuss the rationale for targeting ribosomes to treat cancer, review the limitations of current agents, and highlight an important set of recent discoveries we propose could be exploited to discover molecularly-targeted ribosome-directed cancer therapeutics.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"303-310"},"PeriodicalIF":13.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brain L Schmidt, Francesco De Logu, Romina Nassini, Pierangelo Geppetti, Nigel W Bunnett
{"title":"Pain Signaling by GPCRs and RTKs.","authors":"Brain L Schmidt, Francesco De Logu, Romina Nassini, Pierangelo Geppetti, Nigel W Bunnett","doi":"10.1016/j.tips.2025.02.002","DOIUrl":"10.1016/j.tips.2025.02.002","url":null,"abstract":"<p><p>Chronic pain is common and debilitating, yet is inadequately treated by current therapies, which can have life-threatening side effects. Treatments targeting G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), key pain mediators, often fail in clinical trials for unknown reasons. Here, we discuss the recent evidence that GPCRs and RTKs generate sustained signals from multiprotein signaling complexes or signalosomes in intracellular compartments to control chronic pain. We evaluate the evidence that selective antagonism of these intracellular signals provides more efficacious and long-lasting pain relief than antagonism of receptors at the surface of cells. We highlight how the identification of coreceptors and molecular scaffolds that underpin pain signaling by multiple receptors has identified new therapeutic targets for chronic pain, surmounting the redundancy of the pain signaling pathway.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"372-385"},"PeriodicalIF":13.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Raquel van Gool, Walla Al-Hertani, Olaf Bodamer, Jaymin Upadhyay
{"title":"Levacetylleucine (N-acetyl-l-leucine) for Niemann-Pick disease type C.","authors":"Raquel van Gool, Walla Al-Hertani, Olaf Bodamer, Jaymin Upadhyay","doi":"10.1016/j.tips.2025.02.003","DOIUrl":"10.1016/j.tips.2025.02.003","url":null,"abstract":"","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"386-387"},"PeriodicalIF":13.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A mechanism for ligand-dependent activation of AHR.","authors":"Audrey Guesdon, William Bourguet","doi":"10.1016/j.tips.2025.02.007","DOIUrl":"10.1016/j.tips.2025.02.007","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor (AHR) is a crucial chemosensory protein and an emerging therapeutic target. However, the lack of structural data has long hindered a complete understanding of the mechanisms driving its function. Recently, Wu and colleagues reported a structural analysis of various DNA-bound AHR-ligand complexes, suggesting a ligand-driven activation mechanism.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"295-297"},"PeriodicalIF":13.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Léxane Fournier, Enrico Guarnera, Harald Kolmar, Stefan Becker
{"title":"Allosteric antibodies: a novel paradigm in drug discovery.","authors":"Léxane Fournier, Enrico Guarnera, Harald Kolmar, Stefan Becker","doi":"10.1016/j.tips.2024.10.007","DOIUrl":"10.1016/j.tips.2024.10.007","url":null,"abstract":"<p><p>Allostery represents a fundamental mechanism in protein regulation, enabling modulation of protein function from sites distal to the active site. While traditionally explored in the context of small molecules, allosteric modulation is gaining traction as a main mode of action in the realm of antibodies, which offer enhanced specificity and reduced toxicity. This review delves into the rapidly growing field of allosteric antibodies, highlighting recent therapeutic advancements and novel druggability avenues. We also explore the potential of these antibodies as innovative tools in drug discovery and discuss contemporary strategies for designing novel allosteric antibodies, leveraging state-of-the-art computational approaches.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"311-323"},"PeriodicalIF":13.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}