Nature Reviews Drug Discovery最新文献_第3页

Voltage-gated sodium channels in excitable cells as drug targets

Nature Reviews Drug Discovery Pub Date : 2025-02-03 DOI: 10.1038/s41573-024-01108-x

Matthew Alsaloum, Sulayman D. Dib-Hajj, Dana A. Page, Peter C. Ruben, Adrian R. Krainer, Stephen G. Waxman

{"title":"Voltage-gated sodium channels in excitable cells as drug targets","authors":"Matthew Alsaloum, Sulayman D. Dib-Hajj, Dana A. Page, Peter C. Ruben, Adrian R. Krainer, Stephen G. Waxman","doi":"10.1038/s41573-024-01108-x","DOIUrl":"https://doi.org/10.1038/s41573-024-01108-x","url":null,"abstract":"Excitable cells — including neurons, muscle cells and cardiac myocytes — are unique in expressing high densities of voltage-gated sodium (NaV) channels. This molecular adaptation enables these cells to produce action potentials, and is essential to their function. With the advent of the molecular revolution, the concept of ‘the’ sodium channel has been supplanted by understanding that excitable cells in mammals can express any of nine different forms of sodium channels (NaV1.1–NaV1.9). Selective expression in particular types of cells, together with a key role in controlling action potential firing, makes some of these NaV subtypes especially attractive molecular targets for drug development. Although these different channel subtypes display a common overall structure, differences in their amino acid sequences have provided a basis for the development of subtype-specific drugs. This approach has resulted in exciting progress in the development of drugs for epilepsy, cardiac disorders and pain. In this Review, we discuss recent progress in the development of drugs that selectively target each of the sodium channel subtypes.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel strategies to manage CAR-T cell toxicity

Nature Reviews Drug Discovery Pub Date : 2025-02-03 DOI: 10.1038/s41573-024-01100-5

Arthur Mulvey, Lionel Trueb, George Coukos, Caroline Arber

{"title":"Novel strategies to manage CAR-T cell toxicity","authors":"Arthur Mulvey, Lionel Trueb, George Coukos, Caroline Arber","doi":"10.1038/s41573-024-01100-5","DOIUrl":"https://doi.org/10.1038/s41573-024-01100-5","url":null,"abstract":"The immune-related adverse events associated with chimeric antigen receptor (CAR)-T cell therapy result in substantial morbidity as well as considerable cost to the health-care system, and can limit the use of these treatments. Current therapeutic strategies to manage immune-related adverse events include interleukin-6 receptor (IL-6R) blockade and corticosteroids. However, because these interventions do not always address the side effects, nor prevent progression to higher grades of adverse events, new approaches are needed. A deeper understanding of the cell types involved, and their associated signalling pathways, cellular metabolism and differentiation states, should provide the basis for alternative strategies. To preserve treatment efficacy, cytokine-mediated toxicity needs to be uncoupled from CAR-T cell function, expansion, long-term persistence and memory formation. This may be achieved by targeting CAR or independent cytokine signalling axes transiently, and through novel T cell engineering strategies, such as low-affinity CAR-T cells, reversible on–off switches and versatile adaptor systems. We summarize the current management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and review T cell- and myeloid cell-intrinsic druggable targets and cellular engineering strategies to develop safer CAR-T cells.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The multiple myeloma drug market

Nature Reviews Drug Discovery Pub Date : 2025-01-31 DOI: 10.1038/d41573-025-00017-x

引用次数: 0

Enhancing immunity during ageing by targeting interactions within the tissue environment 以组织环境中的相互作用为目标，增强衰老过程中的免疫力

Nature Reviews Drug Discovery Pub Date : 2025-01-28 DOI: 10.1038/s41573-024-01126-9

Olivia V. Bracken, Roel P. H. De Maeyer, Arne N. Akbar

引用次数: 0

FGF-based drug discovery: advances and challenges

Nature Reviews Drug Discovery Pub Date : 2025-01-28 DOI: 10.1038/s41573-024-01125-w

Gaozhi Chen, Lingfeng Chen, Xiaokun Li, Moosa Mohammadi

{"title":"FGF-based drug discovery: advances and challenges","authors":"Gaozhi Chen, Lingfeng Chen, Xiaokun Li, Moosa Mohammadi","doi":"10.1038/s41573-024-01125-w","DOIUrl":"https://doi.org/10.1038/s41573-024-01125-w","url":null,"abstract":"The fibroblast growth factor (FGF) family comprises 15 paracrine-acting and 3 endocrine-acting polypeptides, which govern a multitude of processes in human development, metabolism and tissue homeostasis. Therapeutic endocrine FGFs have recently advanced in clinical trials, with FGF19 and FGF21-based therapies on the cusp of approval for the treatment of primary sclerosing cholangitis and metabolic syndrome-associated steatohepatitis, respectively. By contrast, while paracrine FGFs were once thought to be promising drug candidates for wound healing, burns, tissue repair and ischaemic ailments based on their potent mitogenic and angiogenic properties, repeated failures in clinical trials have led to the widespread perception that the development of paracrine FGF-based drugs is not feasible. However, the observation that paracrine FGFs can exert FGF hormone-like metabolic activities has restored interest in these FGFs. The recent structural elucidation of the FGF cell surface signalling machinery and the formulation of a new threshold model for FGF signalling specificity have paved the way for therapeutically harnessing paracrine FGFs for the treatment of a range of metabolic diseases.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting mitophagy in neurodegenerative diseases 靶向线粒体自噬在神经退行性疾病中的应用

Nature Reviews Drug Discovery Pub Date : 2025-01-14 DOI: 10.1038/s41573-024-01105-0

Odetta Antico, Paul W. Thompson, Nicholas T. Hertz, Miratul M. K. Muqit, Laura E. Parton

引用次数: 0

Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery G蛋白偶联受体的功能动力学揭示了药物发现的新途径

Nature Reviews Drug Discovery Pub Date : 2025-01-02 DOI: 10.1038/s41573-024-01083-3

Paolo Conflitti, Edward Lyman, Mark S. P. Sansom, Peter W. Hildebrand, Hugo Gutiérrez-de-Terán, Paolo Carloni, T. Bertie Ansell, Shuguang Yuan, Patrick Barth, Anne S. Robinson, Christopher G. Tate, David Gloriam, Stephan Grzesiek, Matthew T. Eddy, Scott Prosser, Vittorio Limongelli

{"title":"Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery","authors":"Paolo Conflitti, Edward Lyman, Mark S. P. Sansom, Peter W. Hildebrand, Hugo Gutiérrez-de-Terán, Paolo Carloni, T. Bertie Ansell, Shuguang Yuan, Patrick Barth, Anne S. Robinson, Christopher G. Tate, David Gloriam, Stephan Grzesiek, Matthew T. Eddy, Scott Prosser, Vittorio Limongelli","doi":"10.1038/s41573-024-01083-3","DOIUrl":"https://doi.org/10.1038/s41573-024-01083-3","url":null,"abstract":"G protein-coupled receptors (GPCRs) are the largest human membrane protein family that transduce extracellular signals into cellular responses. They are major pharmacological targets, with approximately 26% of marketed drugs targeting GPCRs, primarily at their orthosteric binding site. Despite their prominence, predicting the pharmacological effects of novel GPCR-targeting drugs remains challenging due to the complex functional dynamics of these receptors. Recent advances in X-ray crystallography, cryo-electron microscopy, spectroscopic techniques and molecular simulations have enhanced our understanding of receptor conformational dynamics and ligand interactions with GPCRs. These developments have revealed novel ligand-binding modes, mechanisms of action and druggable pockets. In this Review, we highlight such aspects for recently discovered small-molecule drugs and drug candidates targeting GPCRs, focusing on three categories: allosteric modulators, biased ligands, and bivalent and bitopic compounds. Although studies so far have largely been retrospective, integrating structural data on ligand-induced receptor functional dynamics into the drug discovery pipeline has the potential to guide the identification of drug candidates with specific abilities to modulate GPCR interactions with intracellular effector proteins such as G proteins and β-arrestins, enabling more tailored selectivity and efficacy profiles.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"203 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IRDiRC perspectives on the application of digital biomarkers in therapeutic development for rare diseases IRDiRC 关于在罕见病治疗开发中应用数字生物标记的观点

Nature Reviews Drug Discovery Pub Date : 2024-12-16 DOI: 10.1038/d41573-024-00196-z

Rajesh Krishna, Anneliene H. Jonker, Thomas Morel, Ken Sakushima, Anna M. G. Pasmooij, Daniel O’Connor

引用次数: 0

The benefits of translating biomedical research at drug discovery institutes 药物研发机构转化生物医学研究的益处

Nature Reviews Drug Discovery Pub Date : 2024-09-26 DOI: 10.1038/d41573-024-00142-z

David J. Huggins, Jonathan Baell, Paul E. Brennan, Alex Burgin, Duncan E. Scott

引用次数: 0