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Allosteric antibodies: a novel paradigm in drug discovery. 异构抗体：药物发现的新范例。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-04-01 Epub Date: 2024-11-18 DOI: 10.1016/j.tips.2024.10.007
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":19.9,"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}
引用次数: 0
Visceral obesity and HFpEF: targets and therapeutic opportunities. 内脏肥胖和HFpEF：目标和治疗机会。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-04-01 Epub Date: 2025-03-19 DOI: 10.1016/j.tips.2025.02.005
Yilin Li, Zhuofeng Lin, Yulin Li
{"title":"Visceral obesity and HFpEF: targets and therapeutic opportunities.","authors":"Yilin Li, Zhuofeng Lin, Yulin Li","doi":"10.1016/j.tips.2025.02.005","DOIUrl":"10.1016/j.tips.2025.02.005","url":null,"abstract":"<p><p>The effectiveness of weight-loss drugs in heart failure (HF) with preserved ejection fraction (HFpEF) highlights the link between obesity (adipose tissue) and HF (the heart). Recent guidelines incorporating the waist:height ratio for diagnosing and treating obesity reflect the growing recognition of the significance of visceral adiposity. However, its unique impact on HFpEF and their complex relationship remain underexplored. With limited treatment options for obesity-related HFpEF, novel disease-modifying treatments are urgently needed. Here, we clarify the relationship between visceral obesity and HFpEF, introducing the concept of the visceral adipose tissue-heart axis to explore its mechanisms and therapeutic potential. We also discuss promising strategies targeting visceral obesity in HFpEF and propose directions for future research.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"337-356"},"PeriodicalIF":19.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671011","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}
引用次数: 0
Emerging autism and Fragile X syndrome treatments. 新出现的自闭症和脆性X综合征的治疗。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-04-01 Epub Date: 2025-03-17 DOI: 10.1016/j.tips.2025.02.004
Michael Parkhill, Natalina Salmaso, Amedeo D'Angiulli, Vivian Lee, Argel Aguilar-Valles
{"title":"Emerging autism and Fragile X syndrome treatments.","authors":"Michael Parkhill, Natalina Salmaso, Amedeo D'Angiulli, Vivian Lee, Argel Aguilar-Valles","doi":"10.1016/j.tips.2025.02.004","DOIUrl":"10.1016/j.tips.2025.02.004","url":null,"abstract":"<p><p>The limitations of current symptom-focused treatments drive the urgent need for effective therapies for autism and Fragile X syndrome (FXS). Currently, no approved pharmacological interventions target the core symptoms of these disorders. Advances in understanding the underlying biology of autism and FXS make this an important time to explore novel options. Indeed, several treatments have recently been tested in clinical trials, with promising results in treating core symptoms of autism and FXS. We focus on emerging interventions, such as gut microbiome therapies, anti-inflammatory approaches, bumetanide, phosphodiesterase 4D inhibitors, and endocannabinoid modulators. We also discuss factors, such as disorder heterogeneity, which may have contributed to poor efficacy in previously failed late-phase trials and impact recent trials, emphasizing the need for personalized treatment approaches.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"357-371"},"PeriodicalIF":19.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658645","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}
引用次数: 0
M1 receptor positive allosteric modulators discovery approaches. M1受体阳性变构调节剂的发现方法。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-04-01 Epub Date: 2025-03-25 DOI: 10.1016/j.tips.2025.03.001
Takao Mandai, Arthur A Simen, Antonio Laurenza, Haruhide Kimura
{"title":"M1 receptor positive allosteric modulators discovery approaches.","authors":"Takao Mandai, Arthur A Simen, Antonio Laurenza, Haruhide Kimura","doi":"10.1016/j.tips.2025.03.001","DOIUrl":"10.1016/j.tips.2025.03.001","url":null,"abstract":"<p><p>The development of M1 muscarinic acetylcholine-receptor-positive allosteric modulators has been hindered by their limited cognitive efficacy and cholinergic side effects. We discuss two unique approaches - low intrinsic agonism and low binding cooperativity - that were developed to address these issues and their therapeutic implications.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"298-302"},"PeriodicalIF":19.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711374","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}
引用次数: 0
Poison exons: tuning RNA splicing for targeted gene regulation. 毒性外显子：调整RNA剪接以进行靶向基因调控。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-02-05 DOI: 10.1016/j.tips.2025.01.002
Christopher R Neil, Cassandra Schaening-Burgos, Maria S Alexis, Dominic J Reynolds, Peter G Smith, Michael W Seiler, Frédéric H Vaillancourt, Anant A Agrawal
{"title":"Poison exons: tuning RNA splicing for targeted gene regulation.","authors":"Christopher R Neil, Cassandra Schaening-Burgos, Maria S Alexis, Dominic J Reynolds, Peter G Smith, Michael W Seiler, Frédéric H Vaillancourt, Anant A Agrawal","doi":"10.1016/j.tips.2025.01.002","DOIUrl":"10.1016/j.tips.2025.01.002","url":null,"abstract":"<p><p>Poison exons (PEs) are a class of alternatively spliced exons whose inclusion targets mRNA transcripts for degradation via the nonsense-mediated decay (NMD) pathway. Although a role for NMD as an essential mRNA quality control pathway has long been appreciated, recent advances in RNA sequencing (RNA-seq) strategies and analyses have revealed that its coupling to RNA splicing is broadly used to regulate mRNA stability and abundance. Regulation of PE splicing affects patterns of targeted degradation across the transcriptome and influences gene expression in both healthy and disease states. Importantly, PEs represent a novel therapeutic opportunity to modulate the expression of disease-relevant genes with sequence-specific resolution. We review the emergence of PE splicing in endogenous gene regulation, its misregulation in disease, and the ways in which it can be leveraged for therapeutic benefit.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"264-278"},"PeriodicalIF":19.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366002","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}
引用次数: 0
The N terminus-only function of adhesion GPCRs: emerging concepts. 粘附gpcr的仅N端功能：新兴概念。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-02-15 DOI: 10.1016/j.tips.2025.01.004
Laura Lehmann, Victoria Elisabeth Groß, Rene Behlendorf, Simone Prömel
{"title":"The N terminus-only function of adhesion GPCRs: emerging concepts.","authors":"Laura Lehmann, Victoria Elisabeth Groß, Rene Behlendorf, Simone Prömel","doi":"10.1016/j.tips.2025.01.004","DOIUrl":"10.1016/j.tips.2025.01.004","url":null,"abstract":"<p><p>Adhesion G-protein-coupled receptors (aGPCRs) play key roles in health and disease. They are unique in that they not only activate G-protein pathways but also have distinct functions that rely solely on their N termini, making them complex drug targets. To date there have been only descriptive observations about these enigmatic N terminus-only functions. Emerging evidence from several aGPCRs now indicates that these are a defining characteristic of these receptors that allows them to operate bidirectionally across environments. Recent advances in characterizing aGPCR splice variants and receptor structure have revealed the G protein-independent mechanisms that underlie their N terminus-only functions. This review consolidates current findings, explores how the N termini integrate functions, and identifies common principles across aGPCRs. We consider the therapeutic implications and discuss how specifically targeting N terminus functions provides a novel perspective on the pharmacological potential of aGPCRs.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"231-248"},"PeriodicalIF":19.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426265","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}
引用次数: 0
Crosstalk between androgen receptor and protein kinase G signaling in bone: implications for osteoporosis therapy. 骨中雄激素受体和蛋白激酶G信号之间的串扰：对骨质疏松症治疗的意义。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-02-25 DOI: 10.1016/j.tips.2025.01.007
Hema Kalyanaraman, Shyamsundar Pal China, Darren E Casteel, Renate B Pilz
{"title":"Crosstalk between androgen receptor and protein kinase G signaling in bone: implications for osteoporosis therapy.","authors":"Hema Kalyanaraman, Shyamsundar Pal China, Darren E Casteel, Renate B Pilz","doi":"10.1016/j.tips.2025.01.007","DOIUrl":"10.1016/j.tips.2025.01.007","url":null,"abstract":"<p><p>Testosterone, the primary androgen in males, is required for optimal bone mass and strength in men, but the benefits of testosterone therapy in elderly men with modestly reduced testosterone levels remain controversial. Androgens enhance bone formation by osteoblasts and inhibit resorption by osteoclasts. Recent data in osteoblasts indicate that rapid extranuclear androgen receptor (AR) signaling enhances nuclear AR-mediated transcription of the skeletal master regulator β-catenin, and boosts cell proliferation, differentiation, and survival. This novel signaling involves nitric oxide (NO), cGMP, and protein kinase G2 (PKG2). We discuss these recent developments and summarize bone-anabolic AR functions and AR/PKG2 interactions as revealed by the phenotypes of Ar and Pkg2 knockout and transgenic mice. We propose that tissue-selective AR modulators and PKG-activating agents may represent novel treatment options for osteoporosis.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"279-294"},"PeriodicalIF":19.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516911","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}
引用次数: 0
IRAK4: potential therapeutic target for airway disease exacerbations. IRAK4：气道疾病恶化的潜在治疗靶点
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-01-16 DOI: 10.1016/j.tips.2025.01.001
Joseph A Jude, Reynold A Panettieri
{"title":"IRAK4: potential therapeutic target for airway disease exacerbations.","authors":"Joseph A Jude, Reynold A Panettieri","doi":"10.1016/j.tips.2025.01.001","DOIUrl":"10.1016/j.tips.2025.01.001","url":null,"abstract":"<p><p>Inflammatory lung diseases represent a significant healthcare burden. There is an unmet need for identifying therapeutic targets for inflammatory lung diseases, such as asthma, and chronic obstructive pulmonary disease (COPD). In a recent study, Sayers et al. validate the inhibition of interleukin (IL)-1 receptor-associated kinase (IRAK)-4 as a potential therapeutic strategy toward lung inflammation and inflammatory airway diseases more generally.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"201-203"},"PeriodicalIF":19.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012266","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}
引用次数: 0
Animal models of cocaine use: importance of social context and co-use. 可卡因使用的动物模型：社会背景和共同使用的重要性。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-01-28 DOI: 10.1016/j.tips.2025.01.003
Mia I Allen, Michael A Nader
{"title":"Animal models of cocaine use: importance of social context and co-use.","authors":"Mia I Allen, Michael A Nader","doi":"10.1016/j.tips.2025.01.003","DOIUrl":"10.1016/j.tips.2025.01.003","url":null,"abstract":"<p><p>Cocaine-use disorders (CUDs) continue to be a major public health problem that requires effective treatments. Despite decades of preclinical research, there are no FDA-approved pharmacotherapies for cocaine use. While there are numerous potential reasons why no efficacious treatments have been identified or approved for cocaine use, we discuss two possible reasons in this review: the low number of studies incorporating social variables and the overlooking of the clinical reality of polysubstance use. These variables impact drug use across the substance-use cycle, including vulnerability, maintenance, and treatment. Recent preclinical and clinical data suggest that cocaine users who engage in polysubstance use should be viewed as a distinct and more prevalent population who require unique behavioral and pharmacological approaches to reduce cocaine use. Therefore, to understand the neurobiology and eventual treatments for CUDs, both variables should be included in animal models.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"220-230"},"PeriodicalIF":19.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11890930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143060557","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}
引用次数: 0
Leveraging non-enzymatic functions of LSD1 for novel therapeutics. 利用LSD1的非酶功能开发新疗法。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-03-01 Epub Date: 2025-02-17 DOI: 10.1016/j.tips.2025.01.006
Yihui Song, Bin Yu
{"title":"Leveraging non-enzymatic functions of LSD1 for novel therapeutics.","authors":"Yihui Song, Bin Yu","doi":"10.1016/j.tips.2025.01.006","DOIUrl":"10.1016/j.tips.2025.01.006","url":null,"abstract":"<p><p>Lysine-specific demethylase 1 (LSD1) is a key enzyme that removes the methylation marks from lysines in the histone tails of nucleosomes. Emerging evidence suggests that LSD1 exhibits both enzyme-dependent and independent functions across various diseases. However, most LSD1-targeted therapies in clinical trials focus on its classic demethylase activity. Only one allosteric inhibitor (SP-2577) and two nonproteolysis-targeting chimera (PROTAC) LSD1 degraders (BEA-17 and UM171), which target its enzyme-independent functions, have entered clinical assessment. Given the limited exploration of therapeutic strategies targeting the non-enzymatic functions of LSD1, in this opinion, we summarize current insights into its biological roles and structural characteristics. We also highlight potential therapeutic interventions targeting the non-enzymatic functions of LSD1, including allosteric inhibitors, protein-protein interaction (PPI) inhibitors, and small-molecule degraders, and discuss challenges and future directions in drug discovery targeting these functions.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"204-219"},"PeriodicalIF":19.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450312","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}
引用次数: 0
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