Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.12.011
Dingjiacheng Jia , Shujie Chen
In this issue of Cell Chemical Biology, Rebeck et al.1 construct a system that enables Saccharomyces cerevisiae var. boulardii (Sb) to secrete immune checkpoint inhibitors, reducing intestinal tumor load. This safe and effective delivery platform using engineered yeast demonstrates potential for enhancing the efficacy of biologics.
在这一期的Cell Chemical Biology上，Rebeck et al.1构建了一个系统，使酿酒酵母（Saccharomyces cerevisiae var. boulardii, Sb）分泌免疫检查点抑制剂，减少肠道肿瘤负荷。这种安全有效的工程酵母传递平台显示了增强生物制剂功效的潜力。
{"title":"Yeast paves the way for cancer immunotherapy","authors":"Dingjiacheng Jia , Shujie Chen","doi":"10.1016/j.chembiol.2024.12.011","DOIUrl":"10.1016/j.chembiol.2024.12.011","url":null,"abstract":"<div><div>In this issue of <em>Cell Chemical Biology</em>, Rebeck et al.<span><span><sup>1</sup></span></span> construct a system that enables <em>Saccharomyces cerevisiae</em> var. <em>boulardii</em> (<em>Sb</em>) to secrete immune checkpoint inhibitors, reducing intestinal tumor load. This safe and effective delivery platform using engineered yeast demonstrates potential for enhancing the efficacy of biologics.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 9-11"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987081","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 : 2025-01-16DOI: 10.1016/j.chembiol.2024.12.003
Jianjun Yu (余建军) , Huijie Liu (刘慧洁) , Rui Gao (高瑞) , Tao V. Wang (王涛) , Chenggang Li (李成钢) , Yuxiang Liu (刘玉祥) , Lu Yang (杨璐) , Ying Xu (徐颖) , Yunfeng Cui (崔云凤) , Chenxi Jia (贾辰熙) , Juan Huang (黄娟) , Peng R. Chen (陈鹏) , Yi Rao (饶毅)
Research into mechanisms underlying sleep traditionally relies on electrophysiology and genetics. Because sleep can only be measured on whole animals by behavioral observations and physical means, no sleep research was initiated by biochemical and chemical biological approaches. We used phosphorylation sites of kinases important for sleep as targets for biochemical and chemical biological approaches. Sleep was increased in mice carrying a threonine-to-alanine substitution at residue T469 of salt-inducible kinase 3 (SIK3). Our biochemical purification and photo-crosslinking revealed calcineurin (CaN) dephosphorylation, both in vitro and in vivo, of SIK3 at T469 and S551, but not T221. Knocking down CaN regulatory subunit reduced daily sleep by more than 5 h, exceeding all known mouse mutants. Our work uncovered a critical physiological role for CaN in sleep and pioneered biochemical purification and chemical biology as effective approaches to study sleep.
{"title":"Calcineurin: An essential regulator of sleep revealed by biochemical, chemical biological, and genetic approaches","authors":"Jianjun Yu (余建军) , Huijie Liu (刘慧洁) , Rui Gao (高瑞) , Tao V. Wang (王涛) , Chenggang Li (李成钢) , Yuxiang Liu (刘玉祥) , Lu Yang (杨璐) , Ying Xu (徐颖) , Yunfeng Cui (崔云凤) , Chenxi Jia (贾辰熙) , Juan Huang (黄娟) , Peng R. Chen (陈鹏) , Yi Rao (饶毅)","doi":"10.1016/j.chembiol.2024.12.003","DOIUrl":"10.1016/j.chembiol.2024.12.003","url":null,"abstract":"<div><div>Research into mechanisms underlying sleep traditionally relies on electrophysiology and genetics. Because sleep can only be measured on whole animals by behavioral observations and physical means, no sleep research was initiated by biochemical and chemical biological approaches. We used phosphorylation sites of kinases important for sleep as targets for biochemical and chemical biological approaches. Sleep was increased in mice carrying a threonine-to-alanine substitution at residue T469 of salt-inducible kinase 3 (SIK3). Our biochemical purification and photo-crosslinking revealed calcineurin (CaN) dephosphorylation, both <em>in vitro</em> and <em>in vivo</em>, of SIK3 at T469 and S551, but not T221. Knocking down CaN regulatory subunit reduced daily sleep by more than 5 h, exceeding all known mouse mutants. Our work uncovered a critical physiological role for CaN in sleep and pioneered biochemical purification and chemical biology as effective approaches to study sleep.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 157-173.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902000","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 : 2025-01-16DOI: 10.1016/j.chembiol.2024.04.016
Samskrathi Aravinda Sharma , Sarah Olanrewaju Oladejo , Zheng Kuang
Circadian rhythms are intrinsic molecular mechanisms that synchronize biological functions with the day/night cycle. The mammalian gut is colonized by a myriad of microbes, collectively named the gut microbiota. The microbiota impacts host physiology via metabolites and structural components. A key mechanism is the modulation of host epigenetic pathways, especially histone modifications. An increasing number of studies indicate the role of the microbiota in regulating host circadian rhythms. However, the mechanisms remain largely unknown. Here, we summarize studies on microbial regulation of host circadian rhythms and epigenetic pathways, highlight recent findings on how the microbiota employs host epigenetic machinery to regulate circadian rhythms, and discuss its impacts on host physiology, particularly immune and metabolic functions. We further describe current challenges and resources that could facilitate research on microbiota-epigenetic-circadian rhythm interactions to advance our knowledge of circadian disorders and possible therapeutic avenues.
{"title":"Chemical interplay between gut microbiota and epigenetics: Implications in circadian biology","authors":"Samskrathi Aravinda Sharma , Sarah Olanrewaju Oladejo , Zheng Kuang","doi":"10.1016/j.chembiol.2024.04.016","DOIUrl":"10.1016/j.chembiol.2024.04.016","url":null,"abstract":"<div><div>Circadian rhythms are intrinsic molecular mechanisms that synchronize biological functions with the day/night cycle. The mammalian gut is colonized by a myriad of microbes, collectively named the gut microbiota. The microbiota impacts host physiology via metabolites and structural components. A key mechanism is the modulation of host epigenetic pathways, especially histone modifications. An increasing number of studies indicate the role of the microbiota in regulating host circadian rhythms. However, the mechanisms remain largely unknown. Here, we summarize studies on microbial regulation of host circadian rhythms and epigenetic pathways, highlight recent findings on how the microbiota employs host epigenetic machinery to regulate circadian rhythms, and discuss its impacts on host physiology, particularly immune and metabolic functions. We further describe current challenges and resources that could facilitate research on microbiota-epigenetic-circadian rhythm interactions to advance our knowledge of circadian disorders and possible therapeutic avenues.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 61-82"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079922","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 : 2025-01-16DOI: 10.1016/j.chembiol.2024.12.010
Aayushi Uberoi, Elizabeth A. Grice
In an interview with Samantha Nelson, a scientific editor of Cell Chemical Biology, the authors of the research article entitled “Commensal-derived tryptophan metabolites fortify the skin barrier: Insights from a 50-species gnotobiotic model of human skin microbiome” share insights about their paper, field, and lives as scientists.
{"title":"Meet the authors: Aayushi Uberoi and Elizabeth A. Grice","authors":"Aayushi Uberoi, Elizabeth A. Grice","doi":"10.1016/j.chembiol.2024.12.010","DOIUrl":"10.1016/j.chembiol.2024.12.010","url":null,"abstract":"<div><div>In an interview with Samantha Nelson, a scientific editor of <em>Cell Chemical Biology</em>, the authors of the research article entitled “Commensal-derived tryptophan metabolites fortify the skin barrier: Insights from a 50-species gnotobiotic model of human skin microbiome” share insights about their paper, field, and lives as scientists.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 1-2"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986930","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 : 2025-01-16DOI: 10.1016/j.chembiol.2024.11.001
Sidharth S. Madhavan , Stephanie Roa Diaz , Sawyer Peralta , Mitsunori Nomura , Christina D. King , Kaya E. Ceyhan , Anwen Lin , Dipa Bhaumik , Anna C. Foulger , Samah Shah , Thanh Blade , Wyatt Gray , Manish Chamoli , Brenda Eap , Oishika Panda , Diego Diaz , Thelma Y. Garcia , Brianna J. Stubbs , Scott M. Ulrich , Gordon J. Lithgow , John C. Newman
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 solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD.
{"title":"β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain","authors":"Sidharth S. Madhavan , Stephanie Roa Diaz , Sawyer Peralta , Mitsunori Nomura , Christina D. King , Kaya E. Ceyhan , Anwen Lin , Dipa Bhaumik , Anna C. Foulger , Samah Shah , Thanh Blade , Wyatt Gray , Manish Chamoli , Brenda Eap , Oishika Panda , Diego Diaz , Thelma Y. Garcia , Brianna J. Stubbs , Scott M. Ulrich , Gordon J. Lithgow , John C. Newman","doi":"10.1016/j.chembiol.2024.11.001","DOIUrl":"10.1016/j.chembiol.2024.11.001","url":null,"abstract":"<div><div>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 solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain <em>in vivo</em> after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 174-191.e8"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1016/j.chembiol.2024.11.008
Spenser H. Stone , Jeffrey C. Rathmell , Jackie E. Bader
Obesity is a leading risk factor and a negative prognostic indicator for many cancers. In a recent issue of Science Immunology, Bagchi et al. identified that tumor-associated macrophages upregulate GPR65 in response to obesity-driven intratumor acidity resulting in reduced effector function to promote tumor growth.1
{"title":"Macrophages make “sense” of obesity-driven acidity in the TME","authors":"Spenser H. Stone , Jeffrey C. Rathmell , Jackie E. Bader","doi":"10.1016/j.chembiol.2024.11.008","DOIUrl":"10.1016/j.chembiol.2024.11.008","url":null,"abstract":"<div><div>Obesity is a leading risk factor and a negative prognostic indicator for many cancers. In a recent issue of <em>Science Immunology</em>, Bagchi et al. identified that tumor-associated macrophages upregulate GPR65 in response to obesity-driven intratumor acidity resulting in reduced effector function to promote tumor growth.<span><span><sup>1</sup></span></span></div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2021-2023"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849689","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.2024.09.009
Lu Xiao , Linglan Fang , Wenrui Zhong , Eric T. Kool
RNAs fold into compact structures and undergo protein interactions in cells. These occluded environments can block reagents that probe the underlying RNAs. Probes that can analyze structure in crowded settings can shed light on RNA biology. Here, we employ 2′-OH-reactive probes that are small enough to access folded RNA structure underlying close molecular contacts within cells, providing considerably broader coverage for intracellular RNA structural analysis. The data are analyzed first with well-characterized human ribosomal RNAs and then applied transcriptome-wide to polyadenylated transcripts. The smallest probe acetylimidazole (AcIm) yields 80% greater structural coverage than larger conventional reagent NAIN3, providing enhanced structural information in hundreds of transcripts. The acetyl probe also provides superior signals for identifying m6A modification sites in transcripts, particularly in sites that are inaccessible to a standard probe. Our strategy enables profiling RNA infrastructure, enhancing analysis of transcriptome structure, modification, and intracellular interactions, especially in spatially crowded settings.
{"title":"RNA infrastructure profiling illuminates transcriptome structure in crowded spaces","authors":"Lu Xiao , Linglan Fang , Wenrui Zhong , Eric T. Kool","doi":"10.1016/j.chembiol.2024.09.009","DOIUrl":"10.1016/j.chembiol.2024.09.009","url":null,"abstract":"<div><div>RNAs fold into compact structures and undergo protein interactions in cells. These occluded environments can block reagents that probe the underlying RNAs. Probes that can analyze structure in crowded settings can shed light on RNA biology. Here, we employ 2′-OH-reactive probes that are small enough to access folded RNA structure underlying close molecular contacts within cells, providing considerably broader coverage for intracellular RNA structural analysis. The data are analyzed first with well-characterized human ribosomal RNAs and then applied transcriptome-wide to polyadenylated transcripts. The smallest probe acetylimidazole (AcIm) yields 80% greater structural coverage than larger conventional reagent NAIN3, providing enhanced structural information in hundreds of transcripts. The acetyl probe also provides superior signals for identifying m<sup>6</sup>A modification sites in transcripts, particularly in sites that are inaccessible to a standard probe. Our strategy enables profiling RNA infrastructure, enhancing analysis of transcriptome structure, modification, and intracellular interactions, especially in spatially crowded settings.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2156-2167.e5"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487423","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.2024.10.009
Shuo Han , Xiaolei Ye , Jintong Yang , Xuefang Peng , Xiaming Jiang , Jin Li , Xiaojie Zheng , Xinchen Zhang , Yumin Zhang , Lingyu Zhang , Wei Wang , Jiaxin Li , Wenwen Xin , Xiaoai Zhang , Gengfu Xiao , Ke Peng , Leike Zhang , Xuguang Du , Lu Zhou , Wei Liu , Hao Li
Lipids and lipid metabolism play an important role in RNA virus replication, which typically occurs on host cell endomembrane structures in the cytoplasm through mechanisms that are not yet fully identified. We conducted genome-scale CRISPR screening and identified sphingomyelin synthase 1 (SMS1; encoded by SGMS1) as a critical host factor for infection by severe fever with thrombocytopenia syndrome virus (SFTSV). SGMS1 knockout reduced sphingomyelin (SM) (d18:1/16:1) levels, inhibiting SFTSV replication. A helix-turn-helix motif in SFTSV RNA-dependent RNA polymerase (RdRp) directly binds to SM(d18:1/16:1) in Golgi apparatus, which was also observed in SARS-CoV-2 and lymphocytic choriomeningitis virus (LCMV), both showing inhibited replication in SGMS1-KO cells. SM metabolic disturbance is associated with disease severity of viral infections. We designed a novel SMS1 inhibitor that protects mice against lethal SFTSV infection and reduce SARS-CoV-2 replication and pathogenesis. These findings highlight the critical role of SMS1 and SM(d18:1/16:1) in RNA virus replication, suggesting a broad-spectrum antiviral strategy.
{"title":"Host specific sphingomyelin is critical for replication of diverse RNA viruses","authors":"Shuo Han , Xiaolei Ye , Jintong Yang , Xuefang Peng , Xiaming Jiang , Jin Li , Xiaojie Zheng , Xinchen Zhang , Yumin Zhang , Lingyu Zhang , Wei Wang , Jiaxin Li , Wenwen Xin , Xiaoai Zhang , Gengfu Xiao , Ke Peng , Leike Zhang , Xuguang Du , Lu Zhou , Wei Liu , Hao Li","doi":"10.1016/j.chembiol.2024.10.009","DOIUrl":"10.1016/j.chembiol.2024.10.009","url":null,"abstract":"<div><div>Lipids and lipid metabolism play an important role in RNA virus replication, which typically occurs on host cell endomembrane structures in the cytoplasm through mechanisms that are not yet fully identified. We conducted genome-scale CRISPR screening and identified sphingomyelin synthase 1 (SMS1; encoded by SGMS1) as a critical host factor for infection by severe fever with thrombocytopenia syndrome virus (SFTSV). <em>SGMS1</em> knockout reduced sphingomyelin (SM) (d18:1/16:1) levels, inhibiting SFTSV replication. A helix-turn-helix motif in SFTSV RNA-dependent RNA polymerase (RdRp) directly binds to SM(d18:1/16:1) in Golgi apparatus, which was also observed in SARS-CoV-2 and lymphocytic choriomeningitis virus (LCMV), both showing inhibited replication in <em>SGMS1</em>-KO cells. SM metabolic disturbance is associated with disease severity of viral infections. We designed a novel SMS1 inhibitor that protects mice against lethal SFTSV infection and reduce SARS-CoV-2 replication and pathogenesis. These findings highlight the critical role of SMS1 and SM(d18:1/16:1) in RNA virus replication, suggesting a broad-spectrum antiviral strategy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2052-2068.e11"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142670993","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.2024.09.007
Jujun Zhou , Qin Chen , Ren Ren , Jie Yang , Bigang Liu , John R. Horton , Caleb Chang , Chuxuan Li , Leora Maksoud , Yifei Yang , Dante Rotili , Abhinav K. Jain , Xing Zhang , Robert M. Blumenthal , Taiping Chen , Yang Gao , Sergio Valente , Antonello Mai , Xiaodong Cheng
DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a key epigenetic process. Developing non-nucleoside inhibitors to cause DNA hypomethylation is crucial for treating various conditions without the toxicities associated with existing cytidine-based hypomethylating agents. This study characterized fifteen quinoline-based analogs, particularly compounds with additions like a methylamine (9) or methylpiperazine (11), which demonstrate similar low micromolar inhibitory potency against human DNMT1 and Clostridioides difficile CamA. These compounds (9 and 11) intercalate into CamA-bound DNA via the minor groove, causing a conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation. Additionally, some quinoline-based analogs inhibit other DNA-interacting enzymes, such as polymerases and base excision repair glycosylases. Finally, compound 11 elicits DNA damage response via p53 activation in cancer cells.
DNA 甲基化是一个关键的表观遗传过程，例如哺乳动物中的胞嘧啶-C5 甲基化和细菌中的腺嘌呤-N6 甲基化。开发非核苷类抑制剂来引起 DNA 低甲基化，对于治疗各种疾病而不产生现有的基于胞嘧啶的低甲基化药物的毒性至关重要。本研究鉴定了 15 种喹啉类类似物，特别是添加了甲胺（9）或甲基哌嗪（11）的化合物，它们对人类 DNMT1 和艰难梭菌 CamA 具有类似的低微摩尔抑制效力。这些化合物（9 和 11）通过小沟插层到与 CamA 结合的 DNA 中，引起构象转变，使催化结构域远离 DNA。这项研究增加了非核苷酸化合物通过 DNA 插层抑制 DNA 甲基转移酶的有限实例。此外，一些喹啉类似物还能抑制其他与 DNA 有相互作用的酶，如聚合酶和碱基切除修复糖基酶。最后，化合物 11 可通过激活癌细胞中的 p53 引起 DNA 损伤反应。
{"title":"Quinoline-based compounds can inhibit diverse enzymes that act on DNA","authors":"Jujun Zhou , Qin Chen , Ren Ren , Jie Yang , Bigang Liu , John R. Horton , Caleb Chang , Chuxuan Li , Leora Maksoud , Yifei Yang , Dante Rotili , Abhinav K. Jain , Xing Zhang , Robert M. Blumenthal , Taiping Chen , Yang Gao , Sergio Valente , Antonello Mai , Xiaodong Cheng","doi":"10.1016/j.chembiol.2024.09.007","DOIUrl":"10.1016/j.chembiol.2024.09.007","url":null,"abstract":"<div><div>DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a key epigenetic process. Developing non-nucleoside inhibitors to cause DNA hypomethylation is crucial for treating various conditions without the toxicities associated with existing cytidine-based hypomethylating agents. This study characterized fifteen quinoline-based analogs, particularly compounds with additions like a methylamine (<strong>9</strong>) or methylpiperazine (<strong>11</strong>), which demonstrate similar low micromolar inhibitory potency against human DNMT1 and <em>Clostridioides difficile</em> CamA. These compounds (<strong>9</strong> and <strong>11</strong>) intercalate into CamA-bound DNA via the minor groove, causing a conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation. Additionally, some quinoline-based analogs inhibit other DNA-interacting enzymes, such as polymerases and base excision repair glycosylases. Finally, compound <strong>11</strong> elicits DNA damage response via p53 activation in cancer cells.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2112-2127.e6"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452302","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.2024.10.005
Daisuke Ogasawara , David B. Konrad , Zher Yin Tan , Kimberly L. Carey , Jessica Luo , Sang Joon Won , Haoxin Li , Trever R. Carter , Kristen E. DeMeester , Evert Njomen , Stuart L. Schreiber , Ramnik J. Xavier , Bruno Melillo , Benjamin F. Cravatt
Chemical proteomics enables the global analysis of small molecule-protein interactions in native biological systems and has emerged as a versatile approach for ligand discovery. The range of small molecules explored by chemical proteomics has, however, remained limited. Here, we describe a diversity-oriented synthesis (DOS)-inspired library of stereochemically defined compounds bearing diazirine and alkyne units for UV light-induced covalent modification and click chemistry enrichment of interacting proteins, respectively. We find that these “photo-stereoprobes” interact in a stereoselective manner with hundreds of proteins from various structural and functional classes in human cells and demonstrate that these interactions can form the basis for high-throughput screening-compatible NanoBRET assays. Integrated phenotypic screening and chemical proteomics identified photo-stereoprobes that modulate autophagy by engaging the mitochondrial serine protease CLPP. Our findings show the utility of DOS-inspired photo-stereoprobes for expanding the ligandable proteome, furnishing target engagement assays, and facilitating the discovery and characterization of bioactive compounds in phenotypic screens.
{"title":"Chemical tools to expand the ligandable proteome: Diversity-oriented synthesis-based photoreactive stereoprobes","authors":"Daisuke Ogasawara , David B. Konrad , Zher Yin Tan , Kimberly L. Carey , Jessica Luo , Sang Joon Won , Haoxin Li , Trever R. Carter , Kristen E. DeMeester , Evert Njomen , Stuart L. Schreiber , Ramnik J. Xavier , Bruno Melillo , Benjamin F. Cravatt","doi":"10.1016/j.chembiol.2024.10.005","DOIUrl":"10.1016/j.chembiol.2024.10.005","url":null,"abstract":"<div><div>Chemical proteomics enables the global analysis of small molecule-protein interactions in native biological systems and has emerged as a versatile approach for ligand discovery. The range of small molecules explored by chemical proteomics has, however, remained limited. Here, we describe a diversity-oriented synthesis (DOS)-inspired library of stereochemically defined compounds bearing diazirine and alkyne units for UV light-induced covalent modification and click chemistry enrichment of interacting proteins, respectively. We find that these “photo-stereoprobes” interact in a stereoselective manner with hundreds of proteins from various structural and functional classes in human cells and demonstrate that these interactions can form the basis for high-throughput screening-compatible NanoBRET assays. Integrated phenotypic screening and chemical proteomics identified photo-stereoprobes that modulate autophagy by engaging the mitochondrial serine protease CLPP. Our findings show the utility of DOS-inspired photo-stereoprobes for expanding the ligandable proteome, furnishing target engagement assays, and facilitating the discovery and characterization of bioactive compounds in phenotypic screens.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2138-2155.e32"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610396","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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