Pharmacology & Therapeutics最新文献

{"title":"Therapeutic PCSK9 targeting: Inside versus outside the hepatocyte?","authors":"Alberto Corsini ,&nbsp;Henry N. Ginsberg ,&nbsp;M. John Chapman","doi":"10.1016/j.pharmthera.2025.108812","DOIUrl":"10.1016/j.pharmthera.2025.108812","url":null,"abstract":"<div><div>As a major regulator of LDL receptor (LDLR) activity and thus of LDL-cholesterol (LDL-C) levels, proprotein convertase subtilisin/kexin type 9 (PCSK9) represents an obvious therapeutic target for lipid lowering. The PCSK9 inhibitors, alirocumab and evolocumab, are human monoclonal antibodies (mAbs) that act outside the cell by complexing circulating PCSK9 and thus preventing its binding to the LDLR. In contrast, inclisiran, a small interfering RNA (siRNA), inhibits hepatic synthesis of PCSK9, thereby resulting in reduced amounts of the protein inside and outside the cell. Both approaches result in decreased plasma LDL-C concentrations and improved cardiovascular outcomes. Marginally superior LDL-C reduction (≈ 60 %) is achieved with mAbs as compared to the siRNA (≈ 50 %); head-to-head comparisons are required to confirm between-class differences in efficacy. Both drug classes have shown variability in LDL-C lowering response between individuals in waterfall analyses. Whereas mAb-mediated inhibition leads to a compensatory increase in plasma PCSK9 levels, siRNA treatment reduces them. These agents differ in their pharmacokinetic and pharmacodynamic features, which may translate into distinct clinical opportunities under acute (e.g. acute coronary syndromes) as compared to chronic conditions. Both drug classes provide additional reduction in LDL-C levels (up to 50 %) beyond those achieved with statin therapy, facilitating attainment of guideline-recommended LDL-C goals in high and very high-risk patients. Additional PCSK9 inhibitors, including an oral macrocyclic peptide, a small PCSK9 binding protein and a novel small molecule, plus hepatic gene editing of PCSK9, are under development. This review critically appraises pharmacological strategies to target PCSK9 either inside or outside the cell.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"268 ","pages":"Article 108812"},"PeriodicalIF":12.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412738","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}

{"title":"Insights into the results of Resmetirom trials: Can a thyroid hormone receptor agonist be the holy grail of MASH therapy?","authors":"Konstantinos Arvanitakis ,&nbsp;Theocharis Koufakis ,&nbsp;Evangelos Cholongitas ,&nbsp;Sven Francque ,&nbsp;Georgios Germanidis","doi":"10.1016/j.pharmthera.2025.108811","DOIUrl":"10.1016/j.pharmthera.2025.108811","url":null,"abstract":"<div><div>Despite the heavy individual patient and socioeconomic burden of metabolic dysfunction-associated steatohepatitis (MASH), until recently, no pharmacological therapy for MASH was approved, with available treatment options geared towards associated cardiometabolic risk factors. Accelerated approval of resmetirom, a thyroid hormone receptor-β agonist to be used in conjunction with diet and exercise, marks a significant step forward in the treatment of MASH, offering tempered optimism to healthcare providers and millions of patients around the world for more effective management. Evidence from phase 2 and 3 clinical trials suggests that resmetirom has the potential to alleviate hepatic fibrosis and inflammation and significantly reduce liver lipid content. Notwithstanding this landmark event, the clinical implementation of resmetirom comes with important challenges, for example, ensuring patient access to treatment and demonstrating effects on hard MASH-related outcomes, such as progression to cirrhosis and hepatocellular carcinoma. Additional considerations include the evaluation of co-administration with other hepatoprotective treatments and the assessment of the efficacy in specific MASH sub-phenotypes. Furthermore, the accumulation of real-world data and experience is expected to help answer the remaining questions about the (long-term) effectiveness and safety profile of the drug. The purpose of this article is to provide an updated and critical review of the mechanisms of action, efficacy, and safety of resmetirom based on the latest clinical trials, to define its place within the broader landscape of MASH management, and to highlight current knowledge gaps and opportunities for future research in the field.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"268 ","pages":"Article 108811"},"PeriodicalIF":12.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404995","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}

{"title":"From barbiturates to ganaxolone: The importance of chirality in drug development and in understanding the actions of old and new antiseizure medications","authors":"Meir Bialer ,&nbsp;Emilio Perucca","doi":"10.1016/j.pharmthera.2025.108808","DOIUrl":"10.1016/j.pharmthera.2025.108808","url":null,"abstract":"<div><div>Out of 37 antiseizure medications (ASMs) currently in the market, 17 are chiral molecules and an additional one (oxcarbazepine) is a prodrug of the chiral compound licarbazepine. Of the 17 chiral ASMs, six (ethosuximide, fenfluramine, methsuximide, mephobarbital, stiripentol and vigabatrin) are marketed as racemates, and the remainder are licensed as enantiomerically pure medicines. Of note, all chiral ASMs introduced prior to 1990 were marketed as racemates. Stiripentol, fenfluramine and vigabatrin are the only racemic ASMs approved by the FDA &gt;10 years after the release of regulatory guidelines on the development of chiral medicines. Despite the fact that pharmacokinetic and pharmacodynamic differences between enantiomers have been recognized for decades, the importance of chirality in understanding the biological actions of ASMs is not widely appreciated, and many recent publications on racemic ASMs refer to these medications as if they were a single molecular entity. In the present article, we provide a critical review of chiral ASMs developed between the 1920s, when mephobarbital was introduced, and 2022, when the last chiral ASM (ganaxolone) was approved. We summarize available data on stereoselective differences in pharmacokinetics and pharmacodynamics of ASMs marketed as racemates. We also discuss regulatory aspects related to the introduction of racemic medicines within the current regulatory scenario in Europe and the U.S., focusing on stiripentol, vigabatrin and fenfluramine as examples of different approaches. We identified a number of critical knowledge gaps that are relevant to the use of chiral drugs in epilepsy, including a remarkable lack of published information on the comparative pharmacokinetics, toxicity and antiseizure activity of the enantiomers of most racemic ASMs. The importance of chirality aspects in understanding the clinical actions of racemic ASMs is discussed, together with the rationale for the development of enantiomerically pure follow-up compounds with potentially improved efficacy, safety and commercial viability.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"268 ","pages":"Article 108808"},"PeriodicalIF":12.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373619","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}

{"title":"Understanding the molecular bridges between the drugs and immune cell","authors":"Umesh Chandra Dash ,&nbsp;Vinayak Nayak ,&nbsp;Hiten Shanker Navani ,&nbsp;Rashmi Rekha Samal ,&nbsp;Palak Agrawal ,&nbsp;Anup Kumar Singh ,&nbsp;Sanatan Majhi ,&nbsp;Devraj Ganpat Mogare ,&nbsp;Asim K. Duttaroy ,&nbsp;Atala Bihari Jena","doi":"10.1016/j.pharmthera.2025.108805","DOIUrl":"10.1016/j.pharmthera.2025.108805","url":null,"abstract":"<div><div>The interactions of drugs with the host's immune cells determine the drug's efficacy and adverse effects in patients. Nonsteroidal Anti-Inflammatory Drugs (NSAID), such as corticosteroids, NSAIDs, and immunosuppressants, affect the immune cells and alter the immune response. Molecularly, drugs can interact with immune cells via cell surface receptors, changing the antigen presentation by modifying the co-stimulatory molecules and interacting with the signaling pathways of T cells, B cells, Natural killer (NK) cells, mast cells, basophils, and macrophages. Immunotoxicity, resulting from drug-induced changes in redox status, generation of Reactive Oxygen Species (ROS)/Reactive Nitrogen Species (RNS), and alterations in antioxidant enzymes within immune cells, leads to immunodeficiency. This, in turn, causes allergic reactions, autoimmune diseases, and cytokine release syndrome (CRS). The treatment options should include the evaluation of immune status and utilization of the concept of pharmacogenomics to minimize the chances of immunotoxicity. Many strategies in redox, like targeting the redox pathway or using redox-active agents, are available for the modulation of the immune system and developing drugs. Case studies highlight significant drug-immune cell interactions and patient outcomes, underscoring the importance of understanding these complexities. The future direction focuses on the drugs to deliver antiviral therapy, new approaches to immunomodulation, and modern technologies for increasing antidote effects with reduced toxicity. In conclusion, in-depth knowledge of the interaction between drugs and immune cells is critical to protect the patient from the adverse effects of the drug and improve therapeutic outcomes of the treatment process. This review focuses on the multifaceted interactions of drugs and their consequences at the cellular levels of immune cells.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108805"},"PeriodicalIF":12.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143137321","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}

{"title":"Targeting TAK1: Evolution of inhibitors, challenges, and future directions","authors":"Nika Strašek Benedik ,&nbsp;Matic Proj ,&nbsp;Christian Steinebach ,&nbsp;Matej Sova ,&nbsp;Izidor Sosič","doi":"10.1016/j.pharmthera.2025.108810","DOIUrl":"10.1016/j.pharmthera.2025.108810","url":null,"abstract":"<div><div>The increasing incidence of inflammatory and malignant diseases signifies the need to develop first-in-class drugs with novel mechanisms of action. In this respect, the transforming growth factor (TGF)-β-activated kinase 1 (TAK1), an essential part of several signaling pathways, is considered relevant and promising. This manuscript provides a brief overview of the signal transduction orchestrated by TAK1 within these pathways, followed by an in-depth and thorough analysis of the chemical matter demonstrated to inhibit this kinase. Special attention is given to the selectivity profiling of inhibitors, as well as to the outcomes of their biological characterization. Because published TAK1 inhibitors differ significantly in their kinome selectivity, active-site binding, and biological activity, we hope that this review will allow a judicial estimation of their quality and usefulness for TAK1-addressing assays. Our thoughts on the perspectives and possible developments of the field are also provided to assist scientists who are involved in the design and development of TAK1-targeting modulators.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108810"},"PeriodicalIF":12.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254028","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}

{"title":"Biased signaling in drug discovery and precision medicine","authors":"Ren-Lei Ji,&nbsp;Ya-Xiong Tao","doi":"10.1016/j.pharmthera.2025.108804","DOIUrl":"10.1016/j.pharmthera.2025.108804","url":null,"abstract":"<div><div>Receptors are crucial for converting chemical and environmental signals into cellular responses, making them prime targets in drug discovery, with about 70% of drugs targeting these receptors. Biased signaling, or functional selectivity, has revolutionized drug development by enabling precise modulation of receptor signaling pathways. This concept is more firmly established in G protein-coupled receptor and has now been applied to other receptor types, including ion channels, receptor tyrosine kinases, and nuclear receptors. Advances in structural biology have further refined our understanding of biased signaling. This targeted approach enhances therapeutic efficacy and potentially reduces side effects. Numerous biased drugs have been developed and approved as therapeutics to treat various diseases, demonstrating their significant therapeutic potential. This review provides a comprehensive overview of biased signaling in drug discovery and disease treatment, highlighting recent advancements and exploring the therapeutic potential of these innovative modulators across various diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"268 ","pages":"Article 108804"},"PeriodicalIF":12.0,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187876","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":"Annexin A1 in neurological disorders: Neuroprotection and glial modulation","authors":"Luiz Philipe de Souza Ferreira ,&nbsp;Rafael André da Silva ,&nbsp;Pâmela Pacassa Borges ,&nbsp;Luana Filippi Xavier ,&nbsp;Pablo Scharf ,&nbsp;Silvana Sandri ,&nbsp;Sonia M. Oliani ,&nbsp;Sandra H.P. Farsky ,&nbsp;Cristiane D. Gil","doi":"10.1016/j.pharmthera.2025.108809","DOIUrl":"10.1016/j.pharmthera.2025.108809","url":null,"abstract":"<div><div>Neurological disorders, such as neurodegenerative and neuroinflammatory diseases, have contributed significantly to global disability, even considering the rising life years expectations. Therefore, prevention, early diagnosis, and therapeutic alternatives have been essential to avoid the future collapse of health public systems. Annexin A1 (ANXA1), a Ca2 + −dependent protein, is a promising therapeutic candidate for neurological disorders. ANXA1, found in neurons and glia, displays roles in physiological and pathological processes. Despite ANXA1 undoubtedly maintains the blood-brain barrier (BBB) integrity, this review will focus on ANXA1 roles in neurons and glial cells. In neurons, the cytoplasmic expression of ANXA1 is associated with apoptosis, while its nuclear translocation is linked to ischemic neuronal death. Interactions with S100A11, the Tat-NTS peptide, and other molecules, modulate this translocation, suggesting potential therapeutic interventions. ANXA1 expressed on microglia modulates inflammation and efferocytosis. Post-translational modifications, such as SUMOylation, guide the role of ANXA1 in microglia polarization and neuroprotection. In addition, ANXA1 in astrocytes responds to inflammatory stimuli by influencing cytokine release. A comprehensive understanding of the intricate mechanisms of ANXA1 in neurons and glial cells reveals promising therapeutic strategies to alleviate neuronal damage in neurological diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108809"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121688","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":"Uncovering the intricacies of O-GlcNAc modification in cognitive impairment: New insights from regulation to therapeutic targeting","authors":"Jianhui Wang ,&nbsp;Ning Jiang ,&nbsp;Feng Liu ,&nbsp;Chenran Wang ,&nbsp;Wenxia Zhou","doi":"10.1016/j.pharmthera.2024.108761","DOIUrl":"10.1016/j.pharmthera.2024.108761","url":null,"abstract":"<div><div>O-linked β-<em>N</em>-acetylglucosamine (O-GlcNAc) represents a post-translational modification that occurs on serine or threonine residues on various proteins. This conserved modification interacts with vital cellular pathways. Although O-GlcNAc is widely distributed throughout the body, it is particularly enriched in the brain, where most proteins are O-GlcNAcylated. Recent studies have established a causal link between O-GlcNAc regulation in the brain and alterations in neurophysiological function. Alterations in O-GlcNAc levels in the brain are associated with the pathogenesis of several neurogenic diseases that can lead to cognitive impairment. Remarkably, manipulation of O-GlcNAc levels demonstrated a protective effect on cognitive function. Although the precise molecular mechanism of O-GlcNAc modification in the nervous system remains elusive, its regulation is fundamental to multiple neural and cognitive functions, fluctuating levels during normal and pathological cognitive processes. In this review, we highlight the significant functional importance of O-GlcNAc modification in pathological cognitive impairments and the potential application of O-GlcNAc as a promising target for the intervention or amelioration of cognitive impairments.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108761"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738083","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":"Biased signaling in GPCRs: Structural insights and implications for drug development","authors":"Yuanyuan Ma,&nbsp;Brandon Patterson,&nbsp;Lan Zhu","doi":"10.1016/j.pharmthera.2024.108786","DOIUrl":"10.1016/j.pharmthera.2024.108786","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans, playing a crucial role in regulating diverse cellular processes and serving as primary drug targets. Traditional drug design has primarily focused on ligands that uniformly activate or inhibit GPCRs. However, the concept of biased agonism—where ligands selectively stabilize distinct receptor conformations, leading to unique signaling outcomes—has introduced a paradigm shift in therapeutic development. Despite the promise of biased agonists to enhance drug efficacy and minimize side effects, a comprehensive understanding of the structural and biophysical mechanisms underlying biased signaling is essential. Recent advancements in GPCR structural biology have provided unprecedented insights into ligand binding, conformational dynamics, and the molecular basis of biased signaling. These insights, combined with improved techniques for characterizing ligand efficacy, have driven the development of biased ligands for several GPCRs, including opioid, angiotensin, and adrenergic receptors. This review synthesizes these developments, from mechanisms to drug discovery in biased signaling, emphasizing the role of structural insights in the rational design of next-generation biased agonists with superior therapeutic profiles. Ultimately, these advances hold the potential to revolutionize GPCR-targeted drug discovery, paving the way for more precise and effective treatments.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108786"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884948","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}

{"title":"Is there a place for natural agents with anti-inflammatory and antioxidative properties in critically ill patients? Potential usefulness of Xanthohumol","authors":"Wojciech Dabrowski ,&nbsp;Carmen Andrea Pfortmueller ,&nbsp;Katarzyna Kotfis ,&nbsp;Andrzej Jaroszynski ,&nbsp;Mariusz Gagos ,&nbsp;Wlodzimierz Plotek ,&nbsp;Manu L.N.G. Malbrain","doi":"10.1016/j.pharmthera.2024.108766","DOIUrl":"10.1016/j.pharmthera.2024.108766","url":null,"abstract":"<div><div>Multi-organ dysfunction is a major issue in critically ill patients, where a significant inflammatory response appears to be the primary factor driving the degree of organ impairment, which correlates with the extent of organ injury. The management of inflammation requires a multidisciplinary approach, including antibiotics for infection control, circulatory and respiratory support, and correction of coagulation abnormalities. However, the use of anti-inflammatory treatments is typically restricted to a selected group of medications, with their effectiveness remaining the subject of extensive debate. Xanthohumol (Xn), a natural compound extracted from hops, possesses strong anti-inflammatory and antioxidative properties, with a mild anti-coagulation effect. Its biological activity is related to the inhibition of different inflammatory pathways, reduction in cytokine production and secretion, and an increase in antioxidative enzyme activity. This review examined the potential use of Xn as an adjuvant in the treatment of various pathologies in critically ill patients.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108766"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783793","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}