Pub Date : 2024-12-19DOI: 10.1016/j.chembiol.2024.11.007
Franciscus Chandra, Elaine Y. Hsiao
The molecular underpinnings behind the diet-microbiome-host health relationship are largely undescribed. In a recent issue of Science, Cheng et al.1 uncovered one piece of the puzzle by describing a novel fatty acid amide hydrolase (FAAH) derived from a Faecalibacterium prausnitzii strain that correlated with improved malnutrition recovery. This emphasized the microbiome’s role in supporting recovery from malnutrition.
{"title":"FAAHcilitating recovery in malnourished kids","authors":"Franciscus Chandra, Elaine Y. Hsiao","doi":"10.1016/j.chembiol.2024.11.007","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.11.007","url":null,"abstract":"The molecular underpinnings behind the diet-microbiome-host health relationship are largely undescribed. In a recent issue of <em>Science</em>, Cheng et al.<span><span><sup>1</sup></span></span> uncovered one piece of the puzzle by describing a novel fatty acid amide hydrolase (FAAH) derived from a <em>Faecalibacterium prausnitzii</em> strain that correlated with improved malnutrition recovery. This emphasized the microbiome’s role in supporting recovery from malnutrition.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"23 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849690","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 : 2024-12-19DOI: 10.1016/j.chembiol.2024.11.006
Lei Wang, Wen Zhou
Novel inhibitors of pyroptosis promise breakthroughs in treating inflammatory diseases and malignant tumors. In this issue of Cell Chemical Biology, Hu et al.1 identify two repurposed drugs that selectively target gasdermin D (GSDMD) oligomers, effectively suppressing pyroptosis while reducing off-target effects typical of cysteine-based inhibitors.
{"title":"D-aring to explore: New approaches to gasdermin D targeting","authors":"Lei Wang, Wen Zhou","doi":"10.1016/j.chembiol.2024.11.006","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.11.006","url":null,"abstract":"Novel inhibitors of pyroptosis promise breakthroughs in treating inflammatory diseases and malignant tumors. In this issue of <em>Cell Chemical Biology</em>, Hu et al.<span><span><sup>1</sup></span></span> identify two repurposed drugs that selectively target gasdermin D (GSDMD) oligomers, effectively suppressing pyroptosis while reducing off-target effects typical of cysteine-based inhibitors.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"56 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849828","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}
Various types of post-transcriptional modifications contribute to physiological functions by regulating the abundance and function of RNAs. In particular, tRNAs have the widest variety and largest number of modifications, with crucial roles in protein synthesis. Queuosine (Q) is a characteristic tRNA modification with a 7-deazaguanosine core structure bearing a bulky side chain with a cyclopentene group. Q and its derivatives are found in the anticodon of specific tRNAs in both bacteria and eukaryotes. In metazoan tRNAs, Q is further glycosylated with galactose or mannose. The functions of these glycosylated Qs remained unknown for nearly half a century since their discovery. Recently, our group identified the glycosyltransferases responsible for these tRNA modifications and elucidated their biological roles. We, here, review the biochemical and physiological functions of Q and its glycosylated derivatives as well as their associations with human diseases, including cancer and inflammatory and neurological diseases.
{"title":"Biogenesis and roles of tRNA queuosine modification and its glycosylated derivatives in human health and diseases","authors":"Tsutomu Suzuki, Atsuya Ogizawa, Kensuke Ishiguro, Asuteka Nagao","doi":"10.1016/j.chembiol.2024.11.004","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.11.004","url":null,"abstract":"Various types of post-transcriptional modifications contribute to physiological functions by regulating the abundance and function of RNAs. In particular, tRNAs have the widest variety and largest number of modifications, with crucial roles in protein synthesis. Queuosine (Q) is a characteristic tRNA modification with a 7-deazaguanosine core structure bearing a bulky side chain with a cyclopentene group. Q and its derivatives are found in the anticodon of specific tRNAs in both bacteria and eukaryotes. In metazoan tRNAs, Q is further glycosylated with galactose or mannose. The functions of these glycosylated Qs remained unknown for nearly half a century since their discovery. Recently, our group identified the glycosyltransferases responsible for these tRNA modifications and elucidated their biological roles. We, here, review the biochemical and physiological functions of Q and its glycosylated derivatives as well as their associations with human diseases, including cancer and inflammatory and neurological diseases.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"37 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793567","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 : 2024-12-04DOI: 10.1016/j.chembiol.2024.11.005
J. Sebastian Temme, Zibin Tan, Mi Li, Mo Yang, Alexander Wlodawer, Xuefei Huang, John S. Schneekloth, Jeffrey C. Gildersleeve
Polysaccharide intercellular adhesin (PIA), an exopolysaccharide composed of poly-N-acetyl glucosamine (PNAG), is an essential component in many pathogenic biofilms. Partial deacetylation of PNAG is required for biofilm formation, but limited structural knowledge hinders therapeutic development. Employing a new monoclonal antibody (TG10) that selectively binds highly deacetylated PNAG and an antibody (F598) in clinical trials that binds highly acetylated PNAG, we demonstrate that PIA within the biofilm contains distinct regions of highly acetylated and deacetylated exopolysaccharide, contrary to the previous model invoking stochastic deacetylation throughout the biofilm. This discovery led us to hypothesize that targeting both forms of PNAG would enhance efficacy. Remarkably, TG10 and F598 synergistically increased in vitro and in vivo activity, providing 90% survival in a lethal Staphylococcus aureus challenge murine model. Our advanced model deepens the conceptual understanding of PIA architecture and maturation and reveals improved design strategies for PIA-targeting therapeutics, vaccines, and diagnostic agents.
{"title":"Insights into biofilm architecture and maturation enable improved clinical strategies for exopolysaccharide-targeting therapeutics","authors":"J. Sebastian Temme, Zibin Tan, Mi Li, Mo Yang, Alexander Wlodawer, Xuefei Huang, John S. Schneekloth, Jeffrey C. Gildersleeve","doi":"10.1016/j.chembiol.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.11.005","url":null,"abstract":"Polysaccharide intercellular adhesin (PIA), an exopolysaccharide composed of poly-N-acetyl glucosamine (PNAG), is an essential component in many pathogenic biofilms. Partial deacetylation of PNAG is required for biofilm formation, but limited structural knowledge hinders therapeutic development. Employing a new monoclonal antibody (TG10) that selectively binds highly deacetylated PNAG and an antibody (F598) in clinical trials that binds highly acetylated PNAG, we demonstrate that PIA within the biofilm contains distinct regions of highly acetylated and deacetylated exopolysaccharide, contrary to the previous model invoking stochastic deacetylation throughout the biofilm. This discovery led us to hypothesize that targeting both forms of PNAG would enhance efficacy. Remarkably, TG10 and F598 synergistically increased <em>in vitro</em> and <em>in vivo</em> activity, providing 90% survival in a lethal <em>Staphylococcus aureus</em> challenge murine model. Our advanced model deepens the conceptual understanding of PIA architecture and maturation and reveals improved design strategies for PIA-targeting therapeutics, vaccines, and diagnostic agents.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"9 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763761","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}
Neutrophil extracellular traps (NETs), an important host defense mechanism, are assembled after the release of decondensed chromatin and other nuclear components by a process termed NETosis. However, excessive NET release destroys surrounding tissues, leading to conditions such as sepsis where platelets are implicated in the pathogenic switch of NETosis. Here, we show that platelets trigger iron accumulation and promote lipid peroxide production in neutrophils co-stimulated with lipopolysaccharide and platelets in vitro, resulting in the induction of NETosis. We also screened for compounds that inhibit lipid peroxidation, identified 8-methyl-N-geranyl-6-nonamide (capsaicin), and assessed its potential in suppressing platelet-mediated pathogenic NETosis. Capsaicin inhibited lipopolysaccharide/platelet-induced cellular lipid peroxidation and suppressed NETosis in vitro. Furthermore, capsaicin attenuated NETosis in a mouse model of lipopolysaccharide-induced lung inflammation. Our findings provide an original therapeutic strategy to target lipid peroxidation and pave the way for drug development for a wide range of NETosis-related diseases.
{"title":"Platelets accelerate lipid peroxidation and induce pathogenic neutrophil extracellular trap release","authors":"Madoka Ono, Masayasu Toyomoto, Momono Yamauchi, Masatoshi Hagiwara","doi":"10.1016/j.chembiol.2024.11.003","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.11.003","url":null,"abstract":"Neutrophil extracellular traps (NETs), an important host defense mechanism, are assembled after the release of decondensed chromatin and other nuclear components by a process termed NETosis. However, excessive NET release destroys surrounding tissues, leading to conditions such as sepsis where platelets are implicated in the pathogenic switch of NETosis. Here, we show that platelets trigger iron accumulation and promote lipid peroxide production in neutrophils co-stimulated with lipopolysaccharide and platelets <em>in vitro</em>, resulting in the induction of NETosis. We also screened for compounds that inhibit lipid peroxidation, identified 8-methyl-<em>N</em>-geranyl-6-nonamide (capsaicin), and assessed its potential in suppressing platelet-mediated pathogenic NETosis. Capsaicin inhibited lipopolysaccharide/platelet-induced cellular lipid peroxidation and suppressed NETosis <em>in vitro</em>. Furthermore, capsaicin attenuated NETosis in a mouse model of lipopolysaccharide-induced lung inflammation. Our findings provide an original therapeutic strategy to target lipid peroxidation and pave the way for drug development for a wide range of NETosis-related diseases.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"13 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760560","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 : 2024-12-02DOI: 10.1016/j.chembiol.2024.11.001
Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein …
{"title":"β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain","authors":"","doi":"10.1016/j.chembiol.2024.11.001","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.11.001","url":null,"abstract":"Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein …","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"19 3 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758618","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 : 2024-11-27DOI: 10.1016/j.chembiol.2024.11.002
Henry J. Bailey, Jonathan Eisert, Rubina Kazi, Jan Gerhartz, Dominika Ewa Pieńkowska, Ina Dressel, Joshua Vollrath, Ivan Kondratov, Tetiana Matviyuk, Nataliya Tolmachova, Varun Jayeshkumar Shah, Giulio Giuliani, Thorsten Mosler, Thomas M. Geiger, Ana M. Esteves, Sandra P. Santos, Raquel L. Sousa, Tiago M. Bandeiras, Eva-Maria Leibrock, Ulrike Bauer, Ivan Dikic
The majority of clinical degraders utilize an immunomodulatory imide drug (IMiD)-based derivative that directs their target to the E3 ligase receptor cereblon (CRBN); however, identification of IMiD molecular glue substrates has remained underexplored. To tackle this, we design human CRBN constructs, which retain all features for ternary complex formation, while allowing generation of homogenous and cost-efficient expression in E. coli. Extensive profiling of the construct shows it to be the “best of both worlds” in terms of binding activity and ease of production. We next designed the “Enamine focused IMiD library” and demonstrated applicability of the construct to high-throughput screening, identifying binders with high potency, ligand efficiency, and specificity. Finally, we adapt our construct for proof of principle glue screening approaches enabling IMiD cellular interactome determination. Coupled with our IMiD binding landscape the methods described here should serve as valuable tools to assist discovery of next generation CRBN glues.
{"title":"An engineered cereblon optimized for high throughput screening and molecular glue discovery","authors":"Henry J. Bailey, Jonathan Eisert, Rubina Kazi, Jan Gerhartz, Dominika Ewa Pieńkowska, Ina Dressel, Joshua Vollrath, Ivan Kondratov, Tetiana Matviyuk, Nataliya Tolmachova, Varun Jayeshkumar Shah, Giulio Giuliani, Thorsten Mosler, Thomas M. Geiger, Ana M. Esteves, Sandra P. Santos, Raquel L. Sousa, Tiago M. Bandeiras, Eva-Maria Leibrock, Ulrike Bauer, Ivan Dikic","doi":"10.1016/j.chembiol.2024.11.002","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.11.002","url":null,"abstract":"The majority of clinical degraders utilize an immunomodulatory imide drug (IMiD)-based derivative that directs their target to the E3 ligase receptor cereblon (CRBN); however, identification of IMiD molecular glue substrates has remained underexplored. To tackle this, we design human CRBN constructs, which retain all features for ternary complex formation, while allowing generation of homogenous and cost-efficient expression in <em>E. coli</em>. Extensive profiling of the construct shows it to be the “best of both worlds” in terms of binding activity and ease of production. We next designed the “Enamine focused IMiD library” and demonstrated applicability of the construct to high-throughput screening, identifying binders with high potency, ligand efficiency, and specificity. Finally, we adapt our construct for proof of principle glue screening approaches enabling IMiD cellular interactome determination. Coupled with our IMiD binding landscape the methods described here should serve as valuable tools to assist discovery of next generation CRBN glues.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"113 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718728","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 : 2024-11-26DOI: 10.1016/j.chembiol.2024.10.014
Mengdie Wang, Theeraphop Prachyathipsakul, Christi A. Wisniewski, Choua Xiong, Shivam Goel, Hira Lal Goel, Emmet R. Karner, Dimpi Mukhopadhyay, Prachi Gupta, Aniket Majee, S. Thayumanavan, Arthur M. Mercurio
Although programmed cell death ligand 1 (PD-L1) is best known for its role in immune suppression, tumor-intrinsic functions are emerging. Here, we report that tumor cells that express PD-L1 are sensitive to ferroptosis inducers such as imidazole ketone erastin (IKE). PD-L1 promotes ferroptosis sensitivity because it suppresses SLC7A11 expression and diminishes glutathione levels. Although the use of anti-PD-L1 antibody drug conjugates (ADCs) could be effective for the delivery of ferroptosis inducers to specific tumor populations, the chemistry of most ferroptosis inducers precludes their incorporation in ADCs. To overcome this challenge, we synthesized an antibody nanogel conjugate (ANC) comprised of an anti-PD-L1 antibody conjugated to a nanogel encapsulated with IKE. This ANC targets PD-L1-expressing cells in vitro and in vivo and induces ferroptosis, resulting in tumor suppression. Importantly, this approach is superior to systemic administration of IKE because it enables enhanced delivery of IKE specifically to tumor cells and it requires lower drug doses for efficacy.
{"title":"Therapeutic induction of ferroptosis in tumors using PD-L1 targeting antibody nanogel conjugates","authors":"Mengdie Wang, Theeraphop Prachyathipsakul, Christi A. Wisniewski, Choua Xiong, Shivam Goel, Hira Lal Goel, Emmet R. Karner, Dimpi Mukhopadhyay, Prachi Gupta, Aniket Majee, S. Thayumanavan, Arthur M. Mercurio","doi":"10.1016/j.chembiol.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.10.014","url":null,"abstract":"Although programmed cell death ligand 1 <strong>(</strong>PD-L1) is best known for its role in immune suppression, tumor-intrinsic functions are emerging. Here, we report that tumor cells that express PD-L1 are sensitive to ferroptosis inducers such as imidazole ketone erastin (IKE). PD-L1 promotes ferroptosis sensitivity because it suppresses SLC7A11 expression and diminishes glutathione levels. Although the use of anti-PD-L1 antibody drug conjugates (ADCs) could be effective for the delivery of ferroptosis inducers to specific tumor populations, the chemistry of most ferroptosis inducers precludes their incorporation in ADCs. To overcome this challenge, we synthesized an antibody nanogel conjugate (ANC) comprised of an anti-PD-L1 antibody conjugated to a nanogel encapsulated with IKE. This ANC targets PD-L1-expressing cells <em>in vitro</em> and <em>in vivo</em> and induces ferroptosis, resulting in tumor suppression. Importantly, this approach is superior to systemic administration of IKE because it enables enhanced delivery of IKE specifically to tumor cells and it requires lower drug doses for efficacy.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"65 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713116","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 : 2024-11-25DOI: 10.1016/j.chembiol.2024.10.010
Kevin A. Scott, Hiroyuki Kojima, Nathalie Ropek, Charles D. Warren, Tiffany L. Zhang, Simon J. Hogg, Henry Sanford, Caroline Webster, Xiaoyu Zhang, Jahan Rahman, Bruno Melillo, Benjamin F. Cravatt, Jiankun Lyu, Omar Abdel-Wahab, Ekaterina V. Vinogradova
Despite significant interest in therapeutic targeting of splicing, few chemical probes are available for the proteins involved in splicing. Here, we show that elaborated stereoisomeric acrylamide EV96 and its analogues lead to a selective T cell state-dependent loss of interleukin 2-inducible T cell kinase (ITK) by targeting one of the core splicing factors SF3B1. Mechanistic investigations suggest that the state-dependency stems from a combination of differential protein turnover rates and extensive ITK mRNA alternative splicing. We further introduce the most comprehensive list to date of proteins involved in splicing and leverage cysteine- and protein-directed activity-based protein profiling with electrophilic scout fragments to demonstrate covalent ligandability for many classes of splicing factors and splicing regulators in T cells. Taken together, our findings show how chemical perturbation of splicing can lead to immune state-dependent changes in protein expression and provide evidence for the broad potential to target splicing factors with covalent chemistry.
尽管人们对剪接的靶向治疗非常感兴趣，但很少有化学探针可用于参与剪接的蛋白质。在这里，我们展示了精心制作的立体异构体丙烯酰胺 EV96 及其类似物通过靶向核心剪接因子之一 SF3B1，导致白细胞介素 2 诱导型 T 细胞激酶（ITK）的选择性 T 细胞状态依赖性缺失。 机制研究表明，状态依赖性源于不同的蛋白质周转率和广泛的 ITK mRNA 交替剪接。我们进一步介绍了迄今为止最全面的参与剪接的蛋白质列表，并利用半胱氨酸和蛋白质定向活性的蛋白质剖析以及亲电侦察片段证明了 T 细胞中许多种类的剪接因子和剪接调节因子的共价配体性。总之，我们的研究结果表明了剪接的化学扰动如何导致蛋白质表达的免疫状态依赖性变化，并为利用共价化学作用靶向剪接因子的广泛潜力提供了证据。
{"title":"Covalent targeting of splicing in T cells","authors":"Kevin A. Scott, Hiroyuki Kojima, Nathalie Ropek, Charles D. Warren, Tiffany L. Zhang, Simon J. Hogg, Henry Sanford, Caroline Webster, Xiaoyu Zhang, Jahan Rahman, Bruno Melillo, Benjamin F. Cravatt, Jiankun Lyu, Omar Abdel-Wahab, Ekaterina V. Vinogradova","doi":"10.1016/j.chembiol.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.10.010","url":null,"abstract":"Despite significant interest in therapeutic targeting of splicing, few chemical probes are available for the proteins involved in splicing. Here, we show that elaborated stereoisomeric acrylamide EV96 and its analogues lead to a selective T cell state-dependent loss of interleukin 2-inducible T cell kinase (ITK) by targeting one of the core splicing factors SF3B1. Mechanistic investigations suggest that the state-dependency stems from a combination of differential protein turnover rates and extensive ITK mRNA alternative splicing. We further introduce the most comprehensive list to date of proteins involved in splicing and leverage cysteine- and protein-directed activity-based protein profiling with electrophilic scout fragments to demonstrate covalent ligandability for many classes of splicing factors and splicing regulators in T cells. Taken together, our findings show how chemical perturbation of splicing can lead to immune state-dependent changes in protein expression and provide evidence for the broad potential to target splicing factors with covalent chemistry.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"1 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696958","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 : 2024-11-21DOI: 10.1016/j.chembiol.2024.06.013
Yi-Han Huang , Shu-Yu Lin , Li-Chin Ou , Wei-Cheng Huang , Po-Kuan Chao , Yung-Chiao Chang , Hsiao-Fu Chang , Pin-Tse Lee , Teng-Kuang Yeh , Yu-Hsien Kuo , Ya-Wen Tien , Jing-Hua Xi , Pao-Luh Tao , Pin-Yuan Chen , Jian-Ying Chuang , Chuan Shih , Chiung-Tong Chen , Chun-Wei Tung , Horace H. Loh , Shau-Hua Ueng , Shiu-Hwa Yeh
Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation.
吗啡南拮抗剂可阻断μ阿片受体的阿片效应，其镇痛潜力已得到研究。以前的研究表明，这些拮抗剂在存在突变μ阿片受体（MOR；S196A）的情况下可产生镇痛作用，且不良反应较少。然而，引入突变受体用于医疗应用是一项重大挑战。我们假设，将化合物与 MOR 结合可能会产生与 S196A 突变相似的效果。通过高通量筛选和结构-活性关系研究，我们发现了一种调节剂--4-(2-(4-氟苯基)-4-氧代噻唑烷-3-基)-3-甲基苯甲酸（BPRMU191），它能赋予小分子吗啡烷拮抗剂激动特性，而吗啡烷拮抗剂能诱导 G 蛋白依赖的 MOR 激活。将 BPRMU191 和吗啡南拮抗剂联合应用，可产生 MOR 依赖性镇痛，同时减少副作用，包括胃肠道功能障碍、抗痛觉耐受性以及生理和心理依赖性。将 BPRMU191 和吗啡南拮抗剂结合使用，可作为一种潜在的治疗严重疼痛的策略，同时减少不良反应，并为研究 G 蛋白偶联受体调节提供了一条途径。
{"title":"Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia","authors":"Yi-Han Huang , Shu-Yu Lin , Li-Chin Ou , Wei-Cheng Huang , Po-Kuan Chao , Yung-Chiao Chang , Hsiao-Fu Chang , Pin-Tse Lee , Teng-Kuang Yeh , Yu-Hsien Kuo , Ya-Wen Tien , Jing-Hua Xi , Pao-Luh Tao , Pin-Yuan Chen , Jian-Ying Chuang , Chuan Shih , Chiung-Tong Chen , Chun-Wei Tung , Horace H. Loh , Shau-Hua Ueng , Shiu-Hwa Yeh","doi":"10.1016/j.chembiol.2024.06.013","DOIUrl":"10.1016/j.chembiol.2024.06.013","url":null,"abstract":"<div><div><span>Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (</span><strong>BPRMU191</strong>), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of <strong>BPRMU191</strong><span><span> and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including </span>gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining </span><strong>BPRMU191</strong> and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 1885-1898.e10"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141631753","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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