Pub Date : 2024-12-19DOI: 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":"10.1016/j.chembiol.2024.10.014","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2039-2051.e6"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","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}
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":"10.1016/j.chembiol.2024.11.003","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2085-2095.e4"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","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 : 2024-12-19DOI: 10.1016/j.chembiol.2024.09.002
Xu-Hua Mo , Qing-Yin Pu , Tilo Lübken , Gui-Hong Yu , Mert Malay , Paul M. D’Agostino , Tobias A.M. Gulder
Biosynthesis of sodorifen with a unique C16-bicyclo[3.2.1]octene framework requires an S-adenosyl methionine-dependent methyltransferase SodC and terpene cyclase SodD. While bioinformatic analyses reveal a wide distribution of the sodCD genes organization in bacteria, their functional diversity remains largely unknown. Herein, two sodorifen-type gene clusters, pcch and pcau, from Pseudomonas sp. are heterologously expressed in Escherichia coli, leading to the discovery of two C16 terpenoids. Enzymatic synthesis of these compounds is achieved using the two (SodCD-like) pathway-specific enzymes. Enzyme assays using different combinations of methyltransferases and terpene synthases across the pcch, pcau, and sod pathways reveal a unifying biosynthetic mechanism: all three SodC-like enzymes methylate farnesyl pyrophosphate (FPP) with subsequent cyclization to a common intermediate, pre-sodorifen pyrophosphate. Structural diversification of this joint precursor solely occurs by the subsequently acting individual terpene synthases. Our findings expand basic biosynthetic understanding and structural diversity of unusual C16-terpenoids.
{"title":"Discovery and biosynthesis of non-canonical C16-terpenoids from Pseudomonas","authors":"Xu-Hua Mo , Qing-Yin Pu , Tilo Lübken , Gui-Hong Yu , Mert Malay , Paul M. D’Agostino , Tobias A.M. Gulder","doi":"10.1016/j.chembiol.2024.09.002","DOIUrl":"10.1016/j.chembiol.2024.09.002","url":null,"abstract":"<div><div>Biosynthesis of sodorifen with a unique C<sub>16</sub>-bicyclo[3.2.1]octene framework requires an <em>S</em>-adenosyl methionine-dependent methyltransferase SodC and terpene cyclase SodD. While bioinformatic analyses reveal a wide distribution of the <em>sodCD</em> genes organization in bacteria, their functional diversity remains largely unknown. Herein, two sodorifen-type gene clusters, <em>pcch</em> and <em>pcau</em>, from <em>Pseudomonas</em> sp. are heterologously expressed in <em>Escherichia coli</em>, leading to the discovery of two C<sub>16</sub> terpenoids. Enzymatic synthesis of these compounds is achieved using the two (SodCD-like) pathway-specific enzymes. Enzyme assays using different combinations of methyltransferases and terpene synthases across the <em>pcch</em>, <em>pcau</em>, and <em>sod</em> pathways reveal a unifying biosynthetic mechanism: all three SodC-like enzymes methylate farnesyl pyrophosphate (FPP) with subsequent cyclization to a common intermediate, pre-sodorifen pyrophosphate. Structural diversification of this joint precursor solely occurs by the subsequently acting individual terpene synthases. Our findings expand basic biosynthetic understanding and structural diversity of unusual C<sub>16</sub>-terpenoids.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2128-2137.e4"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321402","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.2024.10.002
Yingchao Hu , Honghui Li , Xiangyu Zhang , Yuxian Song , Jun Liu , Jie Pu , Shuang Wen , Hongyang Xu , Hongliang Xin , Bingwei Wang , Shuo Yang
As an executor of pyroptosis, gasdermin D (GSDMD) plays a critical role in inflammatory diseases and cancer. Thus, GSDMD is currently being widely explored as a drug target. Existing inhibitors targeting GSDMD, such as necrosulfonamide, disulfiram, and fumarate, primarily prevent pyroptosis by modifying human/mouse C191/C192 in the N-terminal fragment of GSDMD. However, cysteine modification can prevent the function of important proteins or enzymes, thereby leading to adverse reactions. Here, we chose an alternative key intervention site for GSDMD activation, which is located at the oligomerization interface I of its pore-forming structure. Through high-throughput virtual and experimental screening and in combination with efficacy and pharmacological validation, we have identified two safe, specific “repurposed drugs” that potently suppress GSDMD-mediated pyroptosis. Moreover, the candidates exhibited synergistic therapeutic effects of “1 + 1>2” in murine sepsis and tumorigenesis models. These recently identified GSDMD inhibitors hold great promise for clinical translation in the development of anti-inflammatory and anti-cancer immunotherapies.
{"title":"Identification of two repurposed drugs targeting GSDMD oligomerization interface I to block pyroptosis","authors":"Yingchao Hu , Honghui Li , Xiangyu Zhang , Yuxian Song , Jun Liu , Jie Pu , Shuang Wen , Hongyang Xu , Hongliang Xin , Bingwei Wang , Shuo Yang","doi":"10.1016/j.chembiol.2024.10.002","DOIUrl":"10.1016/j.chembiol.2024.10.002","url":null,"abstract":"<div><div>As an executor of pyroptosis, gasdermin D (GSDMD) plays a critical role in inflammatory diseases and cancer. Thus, GSDMD is currently being widely explored as a drug target. Existing inhibitors targeting GSDMD, such as necrosulfonamide, disulfiram, and fumarate, primarily prevent pyroptosis by modifying human/mouse C191/C192 in the N-terminal fragment of GSDMD. However, cysteine modification can prevent the function of important proteins or enzymes, thereby leading to adverse reactions. Here, we chose an alternative key intervention site for GSDMD activation, which is located at the oligomerization interface I of its pore-forming structure. Through high-throughput virtual and experimental screening and in combination with efficacy and pharmacological validation, we have identified two safe, specific “repurposed drugs” that potently suppress GSDMD-mediated pyroptosis. Moreover, the candidates exhibited synergistic therapeutic effects of “1 + 1>2” in murine sepsis and tumorigenesis models. These recently identified GSDMD inhibitors hold great promise for clinical translation in the development of anti-inflammatory and anti-cancer immunotherapies.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2024-2038.e7"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556318","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.2024.11.007
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":"10.1016/j.chembiol.2024.11.007","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2018-2020"},"PeriodicalIF":6.6,"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.2024.11.005
J. Sebastian Temme , Zibin Tan , Mi Li , Mo Yang , Alexander Wlodawer , Xuefei Huang , John S. Schneekloth Jr. , 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 Jr. , Jeffrey C. Gildersleeve","doi":"10.1016/j.chembiol.2024.11.005","DOIUrl":"10.1016/j.chembiol.2024.11.005","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2096-2111.e7"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","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}
Pub Date : 2024-12-19DOI: 10.1016/j.chembiol.2024.09.004
Sasikumar Kotagiri , Nicholas Blazanin , Yuanxin Xi , Yanyan Han , Md Qudratullah , Xiaobing Liang , Yawen Wang , Poonam Pandey , Hira Mazhar , Truong Nguyen Lam , Anand Kamal Singh , Jing Wang , Yonathan Lissanu
Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified YAP/TEADas key partners to SMARCA2 in driving growth of SMARCA4-mutant cells. Finally, we show that YD23 has potent tumor growth inhibitory activity in SMARCA4-mutant xenografts. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4-mutant lung cancers.
{"title":"Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer","authors":"Sasikumar Kotagiri , Nicholas Blazanin , Yuanxin Xi , Yanyan Han , Md Qudratullah , Xiaobing Liang , Yawen Wang , Poonam Pandey , Hira Mazhar , Truong Nguyen Lam , Anand Kamal Singh , Jing Wang , Yonathan Lissanu","doi":"10.1016/j.chembiol.2024.09.004","DOIUrl":"10.1016/j.chembiol.2024.09.004","url":null,"abstract":"<div><div>Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including <em>SMARCA4</em> and <em>ARID1A</em> in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog <em>SMARCA2</em> is synthetic lethal to <em>SMARCA4</em> suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in <em>SMARCA4</em>-mutant cells with loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified YAP/TEADas key partners to SMARCA2 in driving growth of <em>SMARCA4</em>-mutant cells. Finally, we show that YD23 has potent tumor growth inhibitory activity in <em>SMARCA4</em>-mutant xenografts. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against <em>SMARCA4</em>-mutant lung cancers.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2069-2084.e9"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","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":"10.1016/j.chembiol.2024.11.006","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2015-2017"},"PeriodicalIF":6.6,"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}
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}
Pub Date : 2024-11-21DOI: 10.1016/j.chembiol.2024.06.017
Qian Li , Hanzhong Feng , Qiong Tian , Yun Xiang , Xiaolei Wang , Yong-Xing He , Kui Zhu
The rapid rise of antibiotic resistance calls for the discovery of new antibiotics with distinct antibacterial mechanisms. New target mining is indispensable for developing antibiotics. Plant-microbial antibiotics are appealing to underexplored sources due to a dearth of comprehensive understanding of antibacterial activity and the excavation of new targets. Here, a series of phloroglucinol derivatives of plant-root-associated Pseudomonas fluorescens were synthesized for structure-activity relationship analysis. Notably, 2,4-diproylphloroglucinol (DPPG) displayed efficient bactericidal activity against a wide range of gram-positive bacteria. Importantly, mechanistic study exhibits that DPPG binds to type II NADH dehydrogenase (NDH-2), an essential enzyme catalyzing the transfer of electrons from NADH to quinones in the electron transport chain (ETC), blocking electron transfer in S. aureus. Last, we validated the efficacy of DPPG in vivo through animal infection models. Our findings not only provide a distinct antibiotic lead to treat multidrug resistant pathogens but also identify a promising antibacterial target.
抗生素耐药性的迅速增加要求发现具有独特抗菌机制的新型抗生素。开发抗生素离不开新靶点的挖掘。由于缺乏对抗菌活性的全面了解和新靶点的挖掘，植物微生物抗生素对未充分开发的来源具有吸引力。本文合成了一系列与植物根相关的荧光假单胞菌的氯葡萄糖醇衍生物，并对其进行了结构-活性关系分析。值得注意的是，2,4-二丙基氯葡萄糖醇（DPPG）对多种革兰氏阳性菌具有高效的杀菌活性。重要的是，机理研究表明，DPPG 与 II 型 NADH 脱氢酶（NDH-2）结合，阻断了金黄色葡萄球菌体内的电子传递。最后，我们通过动物感染模型验证了 DPPG 在体内的疗效。我们的研究结果不仅为治疗耐多药病原体提供了一种独特的抗生素线索，还发现了一个很有前景的抗菌靶点。
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