Within neurons, the misfolding and aggregation of certain proteins has been identified as a common feature of many late-onset neurodegenerative diseases (NDs). These aggregate-prone proteins include tau (in both primary tauopathies and in Alzheimer’s disease) and alpha-synuclein in Parkinson’s disease. There is strong experimental evidence that the upregulation of intracellular clearance pathways (autophagy and ubiquitin-proteasome pathways) can clear aggregate-prone proteins in experimental models. When the flux through these pathways is increased, the levels of aggregate-prone proteins are reduced, resulting in improved cell survival in both cell-based and animal models of ND. More recently, a third strategy for clearing proteins from cells has been identified, via the unconventional secretion of proteins out of the cell. However, secretion may also facilitate the spreading and propagation of disease through a prion-like process. This review explains how the autophagy and unconventional secretion pathways interact and how these impact ND.
{"title":"The interplay between autophagy and unconventional secretion in neurodegeneration","authors":"Maurizio Renna , Raffaella Bonavita , Grace Dixon , Luigi Vittorio Verdicchio , Angeleen Fleming","doi":"10.1016/j.chembiol.2025.12.007","DOIUrl":"10.1016/j.chembiol.2025.12.007","url":null,"abstract":"<div><div>Within neurons, the misfolding and aggregation of certain proteins has been identified as a common feature of many late-onset neurodegenerative diseases (NDs). These aggregate-prone proteins include tau (in both primary tauopathies and in Alzheimer’s disease) and alpha-synuclein in Parkinson’s disease. There is strong experimental evidence that the upregulation of intracellular clearance pathways (autophagy and ubiquitin-proteasome pathways) can clear aggregate-prone proteins in experimental models. When the flux through these pathways is increased, the levels of aggregate-prone proteins are reduced, resulting in improved cell survival in both cell-based and animal models of ND. More recently, a third strategy for clearing proteins from cells has been identified, via the unconventional secretion of proteins out of the cell. However, secretion may also facilitate the spreading and propagation of disease through a prion-like process. This review explains how the autophagy and unconventional secretion pathways interact and how these impact ND.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 10-32"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1016/j.chembiol.2025.12.006
Yi-Ting Tsai , Nicolas-Frédéric Lipp , Olivia Seidel , Riya Varma , Aurelie Laguerre , Kristina Solorio-Kirpichyan , Adrian M. Wong , Roberto J. Brea , Grace H. McGregor , Thekla Cordes , Neal K. Devaraj , Lars Kuerschner , Sonya Neal , Christian M. Metallo , Itay Budin
1-Deoxysphingolipids are non-canonical sphingolipids linked to several diseases, yet their cellular effects are poorly understood. Here, we utilize lipid chemical biology approaches to investigate the role of 1-deoxysphingolipid metabolism on the properties and functions of secretory membranes. We applied organelle-specific bioorthogonal labeling to visualize the subcellular distribution of metabolically tagged sphingolipids. We observed that 1-deoxysphingolipids are retained in the endoplasmic reticulum (ER) and specifically in ER exit sites (ERESs), suggesting that they do not efficiently sort into vesicular carriers. Cell lines expressing disease-associated variants of serine palmitoyl-CoA transferase accumulated 1-deoxysphingolipids, which were accompanied by a reduction in ER membrane fluidity and enlargement of ERES. We found that the rates of membrane protein release from the ER were altered in response to 1-deoxysphingolipid metabolism in a manner dependent on the protein’s affinity for ordered or disordered membranes. The dysregulation of sphingolipid metabolism can thus alter secretory membrane properties and affect protein trafficking.
{"title":"1-deoxysphingolipids dysregulate membrane properties and cargo trafficking in the early secretory pathway","authors":"Yi-Ting Tsai , Nicolas-Frédéric Lipp , Olivia Seidel , Riya Varma , Aurelie Laguerre , Kristina Solorio-Kirpichyan , Adrian M. Wong , Roberto J. Brea , Grace H. McGregor , Thekla Cordes , Neal K. Devaraj , Lars Kuerschner , Sonya Neal , Christian M. Metallo , Itay Budin","doi":"10.1016/j.chembiol.2025.12.006","DOIUrl":"10.1016/j.chembiol.2025.12.006","url":null,"abstract":"<div><div>1-Deoxysphingolipids are non-canonical sphingolipids linked to several diseases, yet their cellular effects are poorly understood. Here, we utilize lipid chemical biology approaches to investigate the role of 1-deoxysphingolipid metabolism on the properties and functions of secretory membranes. We applied organelle-specific bioorthogonal labeling to visualize the subcellular distribution of metabolically tagged sphingolipids. We observed that 1-deoxysphingolipids are retained in the endoplasmic reticulum (ER) and specifically in ER exit sites (ERESs), suggesting that they do not efficiently sort into vesicular carriers. Cell lines expressing disease-associated variants of serine palmitoyl-CoA transferase accumulated 1-deoxysphingolipids, which were accompanied by a reduction in ER membrane fluidity and enlargement of ERES. We found that the rates of membrane protein release from the ER were altered in response to 1-deoxysphingolipid metabolism in a manner dependent on the protein’s affinity for ordered or disordered membranes. The dysregulation of sphingolipid metabolism can thus alter secretory membrane properties and affect protein trafficking.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 45-58.e8"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.chembiol.2025.12.010
Garrett L. Lindsey, Thomas K. Hockley, Alejandro Villa Gomez, Andrew C. Marshall, William R. Brothers, Colin T. Finney, Jacob Gross, Archa H. Fox, Gene W. Yeo, Bruno Melillo, Charles S. Bond, Benjamin F. Cravatt
{"title":"Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO","authors":"Garrett L. Lindsey, Thomas K. Hockley, Alejandro Villa Gomez, Andrew C. Marshall, William R. Brothers, Colin T. Finney, Jacob Gross, Archa H. Fox, Gene W. Yeo, Bruno Melillo, Charles S. Bond, Benjamin F. Cravatt","doi":"10.1016/j.chembiol.2025.12.010","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.12.010","url":null,"abstract":"","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"21 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phosphorylation dynamics are delicately balanced by kinases and phosphatases, and abnormal protein phosphorylation events may disrupt normal cellular physiology and thus lead to diseases. Recent developments in phosphorylation targeting tools—mostly the small-molecule kinase inhibitors—have changed the treatments for cancers and other diseases. Alternatively, the use of bifunctional modalities offers another approach through an “event-driven model” with distinct advantages. Here, we highlight advances in bifunctional modalities that modulate protein phosphorylation, including PhosTACs, DEPTACs, PhoRCs, PHICS, and related approaches. Starting with an overview of both kinases and phosphates, we describe recent applications of phosphorylation-targeting therapeutics, with a discussion about the advantages and limitations of current tools, and alternative solutions using bifunctional systems. In addition, the modes of action of various bifunctional modalities and the interplay among protein substrates, kinases, and phosphatases are also discussed, offering an insight into the advancements of phosphorylation targeting strategies against human diseases.
{"title":"Deciphering phosphorylation TACtics: Advances in phosphorylation targeting strategies and bifunctional modalities","authors":"Dong-Ting Ke, Zilong Zhan, Wenliang Zhang, Zhenyi Hu, Po-Han Chen","doi":"10.1016/j.chembiol.2025.12.012","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.12.012","url":null,"abstract":"Phosphorylation dynamics are delicately balanced by kinases and phosphatases, and abnormal protein phosphorylation events may disrupt normal cellular physiology and thus lead to diseases. Recent developments in phosphorylation targeting tools—mostly the small-molecule kinase inhibitors—have changed the treatments for cancers and other diseases. Alternatively, the use of bifunctional modalities offers another approach through an “event-driven model” with distinct advantages. Here, we highlight advances in bifunctional modalities that modulate protein phosphorylation, including PhosTACs, DEPTACs, PhoRCs, PHICS, and related approaches. Starting with an overview of both kinases and phosphates, we describe recent applications of phosphorylation-targeting therapeutics, with a discussion about the advantages and limitations of current tools, and alternative solutions using bifunctional systems. In addition, the modes of action of various bifunctional modalities and the interplay among protein substrates, kinases, and phosphatases are also discussed, offering an insight into the advancements of phosphorylation targeting strategies against human diseases.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"7 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Among the many proteins involved in cancer progression, an increasing number of RNA-binding proteins (RBPs) are central to the function of a cell and tightly associated to genetic diseases. In a recent study, small-molecule inhibitors have been identified as targeting NONO, an RBP known to be involved in mRNA splicing, DNA repair, and membraneless organelle stability. Here, we report the molecular basis of NONO targeting by the α-chloroacetamide molecule (R)-SKBG-1, its specific binding to NONO, and the enantiomer selectivity on the basis of mass spectrometry measurements and structure determination. We have determined the crystal structure of (R)-SKBG-1-bound to NONO homodimer. This study sheds light on the conformational plasticity of (R)-SKBG-1 when covalently bound to NONO. Altogether, these results give an experimental rationale for ligand modification and optimization in a future use as a drug against cancer.
{"title":"Structural basis for NONO-specific modification by the α-chloroacetamide compound (R)-SKBG-1.","authors":"Alessia Vincenza Florio, Corinne Buré, Sébastien Fribourg","doi":"10.1016/j.chembiol.2025.12.013","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.12.013","url":null,"abstract":"<p><p>Among the many proteins involved in cancer progression, an increasing number of RNA-binding proteins (RBPs) are central to the function of a cell and tightly associated to genetic diseases. In a recent study, small-molecule inhibitors have been identified as targeting NONO, an RBP known to be involved in mRNA splicing, DNA repair, and membraneless organelle stability. Here, we report the molecular basis of NONO targeting by the α-chloroacetamide molecule (R)-SKBG-1, its specific binding to NONO, and the enantiomer selectivity on the basis of mass spectrometry measurements and structure determination. We have determined the crystal structure of (R)-SKBG-1-bound to NONO homodimer. This study sheds light on the conformational plasticity of (R)-SKBG-1 when covalently bound to NONO. Altogether, these results give an experimental rationale for ligand modification and optimization in a future use as a drug against cancer.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":" ","pages":""},"PeriodicalIF":7.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.chembiol.2025.11.013
Deguang Liang, Xuejun Jiang
{"title":"Redundant or resilient? A systems view of ferroptosis surveillance mechanisms","authors":"Deguang Liang, Xuejun Jiang","doi":"10.1016/j.chembiol.2025.11.013","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.11.013","url":null,"abstract":"","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"41 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.008
Wyatt Paulishak , Jianen Lyu , Michael S. VanNieuwenhze , Laurence M. Wood
Targeted drug delivery is among the fastest growing fields in cancer therapy. Advances in delivery have resulted in developments like antibody-drug conjugates (ADCs) and drug-loaded nanoparticles. Delivery, however, is hampered by target resistance, induced immunosuppression, and low tumor penetration. Listeria monocytogenes (LM) is a Gram-positive intracellular bacterium being investigated in preclinical and clinical trials as a therapeutic cancer vaccine platform. However, limited work has explored LM as a cytotoxin delivery vehicle. Here, we show that LM can deliver cytotoxin cargo resulting in increased cytotoxicity in vitro and reduced tumor growth in vivo in a microsatellite-stable (MSS) colorectal cancer (CRC) model. LM delivery of saporin dramatically improved cytotoxicity over SN38/Dox-ADC cargo. Reduced MSS CRC tumor growth was dependent on LM-mediated delivery of saporin and correlated with high immune infiltration. These results demonstrate efficacious cytotoxin delivery using LM and establish precedent for LM as a delivery vehicle for cytotoxic agents.
{"title":"Bugs delivering drugs: Listeria monocytogenes-mediated cytotoxin delivery enhances anti-tumor activity in colorectal cancer","authors":"Wyatt Paulishak , Jianen Lyu , Michael S. VanNieuwenhze , Laurence M. Wood","doi":"10.1016/j.chembiol.2025.11.008","DOIUrl":"10.1016/j.chembiol.2025.11.008","url":null,"abstract":"<div><div>Targeted drug delivery is among the fastest growing fields in cancer therapy. Advances in delivery have resulted in developments like antibody-drug conjugates (ADCs) and drug-loaded nanoparticles. Delivery, however, is hampered by target resistance, induced immunosuppression, and low tumor penetration. <em>Listeria monocytogenes</em> (LM) is a Gram-positive intracellular bacterium being investigated in preclinical and clinical trials as a therapeutic cancer vaccine platform. However, limited work has explored LM as a cytotoxin delivery vehicle. Here, we show that LM can deliver cytotoxin cargo resulting in increased cytotoxicity <em>in vitro</em> and reduced tumor growth <em>in vivo</em> in a microsatellite-stable (MSS) colorectal cancer (CRC) model. LM delivery of saporin dramatically improved cytotoxicity over SN38/Dox-ADC cargo. Reduced MSS CRC tumor growth was dependent on LM-mediated delivery of saporin and correlated with high immune infiltration. These results demonstrate efficacious cytotoxin delivery using LM and establish precedent for LM as a delivery vehicle for cytotoxic agents.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1517-1531.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145729092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.012
Steeve Akumwami , Susan L. Ingram
Mu-opioid receptors (MORs) are expressed in brain and contribute to a complex array of advantageous and deleterious behaviors. In this issue of Cell Chemical Biology, Sanchez et al.1 report a genetically encoded pharmacological tool to probe spatiotemporal release of endogenous opioids and their actions at MORs across cell types and circuits.
{"title":"Deciphering the opioid code","authors":"Steeve Akumwami , Susan L. Ingram","doi":"10.1016/j.chembiol.2025.11.012","DOIUrl":"10.1016/j.chembiol.2025.11.012","url":null,"abstract":"<div><div>Mu-opioid receptors (MORs) are expressed in brain and contribute to a complex array of advantageous and deleterious behaviors. In this issue of <em>Cell Chemical Biology,</em> Sanchez et al.<span><span><sup>1</sup></span></span> report a genetically encoded pharmacological tool to probe spatiotemporal release of endogenous opioids and their actions at MORs across cell types and circuits.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1429-1431"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.chembiol.2025.10.009
Yuan Li , Jiwei Qiu , Zhihong Liu , Huiwen Xiao , Bin Wang , Yanxi Dong , Yunong Xiao , Qi Wang , Jiali Dong , Ming Cui
Food as medicine shows promise for disease intervention or treatment. Here, we found phytate, an active ingredient of plant-based diets, exhibits properties in mitigating radiotherapy-related complications. Oral gavage of phytate restored hematogenic organ atrophy, elevated peripheral blood neutrophils and white blood cells, reduced inflammation, and improved gastrointestinal (GI) integrity in irradiated mice. Phytate intake modulated the gut microbiota, facilitating the colonization of symbiotic Parasutterella in GI tract, thus combating intestinal radiation toxicity. In vitro assays and untargeted metabolomics identified 3-phenyllactic acid (PLA) and N-acetyl-L-leucine (NL) as functional metabolites produced by Parasutterella. In vitro, ex vivo, and in vivo models showed that PLA induces M2-like polarization in macrophages, while NL reduced oxidative stress, both counteracting radiation toxicity and working synergistically. Our findings offer mechanistic insights into phytate for alleviating radiation-associated complications and suggest that Parasutterella and its metabolites might be employed as promising probiotics or postbiotics for cancer patients undergoing radiotherapy.
{"title":"Phytate enhances gut Parasutterella colonization to alleviate radiation injury","authors":"Yuan Li , Jiwei Qiu , Zhihong Liu , Huiwen Xiao , Bin Wang , Yanxi Dong , Yunong Xiao , Qi Wang , Jiali Dong , Ming Cui","doi":"10.1016/j.chembiol.2025.10.009","DOIUrl":"10.1016/j.chembiol.2025.10.009","url":null,"abstract":"<div><div>Food as medicine shows promise for disease intervention or treatment. Here, we found phytate, an active ingredient of plant-based diets, exhibits properties in mitigating radiotherapy-related complications. Oral gavage of phytate restored hematogenic organ atrophy, elevated peripheral blood neutrophils and white blood cells, reduced inflammation, and improved gastrointestinal (GI) integrity in irradiated mice. Phytate intake modulated the gut microbiota, facilitating the colonization of symbiotic <em>Parasutterella</em> in GI tract, thus combating intestinal radiation toxicity. <em>In vitro</em> assays and untargeted metabolomics identified 3-phenyllactic acid (PLA) and N-acetyl-L-leucine (NL) as functional metabolites produced by <em>Parasutterella</em>. <em>In vitro</em>, <em>ex vivo</em>, and <em>in vivo</em> models showed that PLA induces M2-like polarization in macrophages, while NL reduced oxidative stress, both counteracting radiation toxicity and working synergistically. Our findings offer mechanistic insights into phytate for alleviating radiation-associated complications and suggest that <em>Parasutterella</em> and its metabolites might be employed as promising probiotics or postbiotics for cancer patients undergoing radiotherapy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1458-1472.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145532057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.002
J. Sanchez , A. Bonifazi , S. Groom , M.O. Sambrook , G.A. Camacho-Hernandez , E.J. Kuijer , S. Karimi , K.U. Therese , M. Hauge Pedersen , C. Rauffenbart , M. Canals , A.H. Newman , C.P. Bailey , J.A. Javitch , J.R. Lane
Opioid receptors are expressed in virtually all neural loci contributing to the experience of pain. Due to this widespread expression, the contribution of specific cell types to the analgesic properties and deleterious side effects of opioids remains incompletely understood. Linking the activity of specific receptors in defined cells to behavioral or physiological processes remains a major challenge of translational pharmacology. In this study, we describe the development of drugs acutely restricted by membrane tethering (DART) antagonists that contain an antagonist naloxone moiety linked to a Halo-tag reactive group. The optimized Naloxo-DART displayed robust blockade of a MOR agonist only when cells co-expressed a Halo-tagged membrane tether. We use the Naloxo-DART delivered in vivo to selectively block MORs in locus coeruleus neurons in brain slide preparations. The Naloxo-DART provides a powerful approach for elucidating the physiological roles of MORs expressed in specific neuronal populations with acute spatiotemporal control.
{"title":"Targeted inhibition of mu-opioid receptors in neuronal subpopulations by membrane-tethered Naloxo-DART antagonists","authors":"J. Sanchez , A. Bonifazi , S. Groom , M.O. Sambrook , G.A. Camacho-Hernandez , E.J. Kuijer , S. Karimi , K.U. Therese , M. Hauge Pedersen , C. Rauffenbart , M. Canals , A.H. Newman , C.P. Bailey , J.A. Javitch , J.R. Lane","doi":"10.1016/j.chembiol.2025.11.002","DOIUrl":"10.1016/j.chembiol.2025.11.002","url":null,"abstract":"<div><div>Opioid receptors are expressed in virtually all neural loci contributing to the experience of pain. Due to this widespread expression, the contribution of specific cell types to the analgesic properties and deleterious side effects of opioids remains incompletely understood. Linking the activity of specific receptors in defined cells to behavioral or physiological processes remains a major challenge of translational pharmacology. In this study, we describe the development of drugs acutely restricted by membrane tethering (DART) antagonists that contain an antagonist naloxone moiety linked to a Halo-tag reactive group. The optimized Naloxo-DART displayed robust blockade of a MOR agonist only when cells co-expressed a Halo-tagged membrane tether. We use the Naloxo-DART delivered <em>in vivo</em> to selectively block MORs in locus coeruleus neurons in brain slide preparations. The Naloxo-DART provides a powerful approach for elucidating the physiological roles of MORs expressed in specific neuronal populations with acute spatiotemporal control.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1473-1485.e9"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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