{"title":"Human brain organoids identify glioma inhibitors","authors":"","doi":"10.1038/d41573-025-00007-z","DOIUrl":"https://doi.org/10.1038/d41573-025-00007-z","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"84 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939519","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}
{"title":"Sodium channel blocker reduces skin inflammation","authors":"","doi":"10.1038/d41573-025-00005-1","DOIUrl":"https://doi.org/10.1038/d41573-025-00005-1","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939607","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}
{"title":"Cough suppressant reverses lung scarring","authors":"","doi":"10.1038/d41573-025-00006-0","DOIUrl":"https://doi.org/10.1038/d41573-025-00006-0","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939637","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}
{"title":"Engineered T cells traverse new terrain","authors":"","doi":"10.1038/d41573-025-00002-4","DOIUrl":"https://doi.org/10.1038/d41573-025-00002-4","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935493","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}
{"title":"Lipid nanoparticle ferries therapeutic mRNA to the placenta","authors":"","doi":"10.1038/d41573-025-00003-3","DOIUrl":"https://doi.org/10.1038/d41573-025-00003-3","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934976","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}
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":"<p>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.</p>","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}
{"title":"2024 FDA approvals","authors":"","doi":"10.1038/d41573-025-00001-5","DOIUrl":"https://doi.org/10.1038/d41573-025-00001-5","url":null,"abstract":"The FDA approved 50 new therapeutics in 2024, with green lights for a novel schizophrenia drug, a first NASH medicine and much more.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911570","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}
{"title":"Pairing up with GLP-1 to combat obesity","authors":"","doi":"10.1038/d41573-024-00205-1","DOIUrl":"https://doi.org/10.1038/d41573-024-00205-1","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841349","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}
{"title":"FDA approves first HER2 × HER3 bispecific antibody","authors":"","doi":"10.1038/d41573-024-00206-0","DOIUrl":"https://doi.org/10.1038/d41573-024-00206-0","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841348","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}
Halle M. Barber, Adrian A. Pater, Keith T. Gagnon, Masad J. Damha, Daniel O’Reilly
{"title":"Chemical engineering of CRISPR–Cas systems for therapeutic application","authors":"Halle M. Barber, Adrian A. Pater, Keith T. Gagnon, Masad J. Damha, Daniel O’Reilly","doi":"10.1038/s41573-024-01086-0","DOIUrl":"https://doi.org/10.1038/s41573-024-01086-0","url":null,"abstract":"<p>Clustered regularly interspaced short palindromic repeats (CRISPR) technology has transformed molecular biology and the future of gene-targeted therapeutics. CRISPR systems comprise a CRISPR-associated (Cas) endonuclease and a guide RNA (gRNA) that can be programmed to guide sequence-specific binding, cleavage, or modification of complementary DNA or RNA. However, the application of CRISPR-based therapeutics is challenged by factors such as molecular size, prokaryotic or phage origins, and an essential gRNA cofactor requirement, which impact efficacy, delivery and safety. This Review focuses on chemical modification and engineering approaches for gRNAs to enhance or enable CRISPR-based therapeutics, emphasizing Cas9 and Cas12a as therapeutic paradigms. Issues that chemically modified gRNAs seek to address, including drug delivery, physiological stability, editing efficiency and off-target effects, as well as challenges that remain, are discussed.</p>","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"46 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832614","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}
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