Pub Date : 2024-10-22DOI: 10.1016/j.chembiol.2024.09.008
Kelly H. Sokol, Cameron J. Lee, Thomas J. Rogers, Althea Waldhart, Abigail E. Ellis, Sahithi Madireddy, Samuel R. Daniels, Rachel (Rae) J. House, Xinyu Ye, Mary Olesnavich, Amy Johnson, Benjamin R. Furness, Ryan D. Sheldon, Evan C. Lien
Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.
{"title":"Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking","authors":"Kelly H. Sokol, Cameron J. Lee, Thomas J. Rogers, Althea Waldhart, Abigail E. Ellis, Sahithi Madireddy, Samuel R. Daniels, Rachel (Rae) J. House, Xinyu Ye, Mary Olesnavich, Amy Johnson, Benjamin R. Furness, Ryan D. Sheldon, Evan C. Lien","doi":"10.1016/j.chembiol.2024.09.008","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.09.008","url":null,"abstract":"Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"2 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487024","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 : 2024-10-21DOI: 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":"https://doi.org/10.1016/j.chembiol.2024.09.007","url":null,"abstract":"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.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"75 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-10-21","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-17DOI: 10.1016/j.chembiol.2024.09.003
Yue Xiao , Linyu Wei , Jingfen Su , Huiyang Lei , Fei Sun , Mengzhu Li , Shihong Li , Xiaochuan Wang , Jie Zheng , Jian-Zhi Wang
Abnormal accumulation of hyperphosphorylated tau (pTau) is a major cause of neurodegeneration in Alzheimer’s disease (AD) and related tauopathies. Therefore, reducing pTau holds therapeutic promise for these diseases. Here, we developed a chimeric peptide, named D20, for selective facilitation of tau dephosphorylation by recruiting protein phosphatase 1 (PP1) to tau. PP1 is one of the active phosphatases that dephosphorylates tau. In both cultured primary hippocampal neurons and mouse models for AD or related tauopathies, we demonstrated that single-dose D20 treatment significantly reduced pTau by dephosphorylation at multiple AD-related sites and total tau (tTau) levels were also decreased. Multiple-dose administration of D20 through tail vein injection in 3xTg AD mice effectively ameliorated tau-associated pathologies with improved cognitive functions. Importantly, at therapeutic doses, D20 did not cause detectable toxicity in cultured neurons, neural cells, or peripheral organs in mice. These results suggest that D20 is a promising drug candidate for AD and related tauopathies.
高磷酸化 tau（pTau）的异常积累是阿尔茨海默病（AD）和相关 tau 病神经变性的主要原因。因此，降低 pTau 有望治疗这些疾病。在这里，我们开发了一种名为D20的嵌合肽，通过将蛋白磷酸酶1（PP1）招募到tau上，选择性地促进tau去磷酸化。PP1是使tau去磷酸化的活性磷酸酶之一。我们在培养的原代海马神经元和AD或相关tau病小鼠模型中证实，单剂量D20治疗可通过在多个AD相关位点去磷酸化而显著降低pTau，总tau（tTau）水平也会降低。在 3xTg AD 小鼠中通过尾静脉注射多剂量 D20 能有效改善与 tau 相关的病理现象，并改善认知功能。重要的是，在治疗剂量下，D20 不会对小鼠的培养神经元、神经细胞或外周器官产生可检测到的毒性。这些结果表明，D20是一种很有前景的候选药物，可用于治疗AD和相关的tau病症。
{"title":"A tau dephosphorylation-targeting chimeraselectively recruits protein phosphatase-1 to ameliorate Alzheimer’s disease and tauopathies","authors":"Yue Xiao , Linyu Wei , Jingfen Su , Huiyang Lei , Fei Sun , Mengzhu Li , Shihong Li , Xiaochuan Wang , Jie Zheng , Jian-Zhi Wang","doi":"10.1016/j.chembiol.2024.09.003","DOIUrl":"10.1016/j.chembiol.2024.09.003","url":null,"abstract":"<div><div>Abnormal accumulation of hyperphosphorylated tau (pTau) is a major cause of neurodegeneration in Alzheimer’s disease (AD) and related tauopathies. Therefore, reducing pTau holds therapeutic promise for these diseases. Here, we developed a chimeric peptide, named D20, for selective facilitation of tau dephosphorylation by recruiting protein phosphatase 1 (PP1) to tau. PP1 is one of the active phosphatases that dephosphorylates tau. In both cultured primary hippocampal neurons and mouse models for AD or related tauopathies, we demonstrated that single-dose D20 treatment significantly reduced pTau by dephosphorylation at multiple AD-related sites and total tau (tTau) levels were also decreased. Multiple-dose administration of D20 through tail vein injection in 3xTg AD mice effectively ameliorated tau-associated pathologies with improved cognitive functions. Importantly, at therapeutic doses, D20 did not cause detectable toxicity in cultured neurons, neural cells, or peripheral organs in mice. These results suggest that D20 is a promising drug candidate for AD and related tauopathies.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1787-1799.e6"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330242","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 : 2024-10-17DOI: 10.1016/j.chembiol.2024.07.017
Timo Hagen , Jacob L. Litke , Nahian Nasir , Qian Hou , Samie R. Jaffrey
Small molecule-regulated RNA devices have the potential to modulate diverse aspects of cellular function, but the small molecules used to date have potential toxicities limiting their use in cells. Here we describe a method for creating drug-regulated RNA nanodevices (RNs) using acyclovir, a biologically compatible small molecule with minimal toxicity. Our modular approach involves a scaffold comprising a central F30 three-way junction, an integrated acyclovir aptamer on the input arm, and a variable effector-binding aptamer on the output arm. This design allows for the rapid engineering of acyclovir-regulated RNs, facilitating temporal, tunable, and reversible control of intracellular aptamers. We demonstrate the control of the Broccoli aptamer and the iron-responsive element (IRE) by acyclovir. Regulating the IRE with acyclovir enables precise control over iron-regulatory protein (IRP) sequestration, consequently promoting the inhibition of ferroptosis. Overall, the method described here provides a platform for transforming aptamers into acyclovir-controllable antagonists against physiologic target proteins.
{"title":"Engineering acyclovir-induced RNA nanodevices for reversible and tunable control of aptamer function","authors":"Timo Hagen , Jacob L. Litke , Nahian Nasir , Qian Hou , Samie R. Jaffrey","doi":"10.1016/j.chembiol.2024.07.017","DOIUrl":"10.1016/j.chembiol.2024.07.017","url":null,"abstract":"<div><div>Small molecule-regulated RNA devices have the potential to modulate diverse aspects of cellular function, but the small molecules used to date have potential toxicities limiting their use in cells. Here we describe a method for creating drug-regulated RNA nanodevices (RNs) using acyclovir, a biologically compatible small molecule with minimal toxicity. Our modular approach involves a scaffold comprising a central F30 three-way junction, an integrated acyclovir aptamer on the input arm, and a variable effector-binding aptamer on the output arm. This design allows for the rapid engineering of acyclovir-regulated RNs, facilitating temporal, tunable, and reversible control of intracellular aptamers. We demonstrate the control of the Broccoli aptamer and the iron-responsive element (IRE) by acyclovir. Regulating the IRE with acyclovir enables precise control over iron-regulatory protein (IRP) sequestration, consequently promoting the inhibition of ferroptosis. Overall, the method described here provides a platform for transforming aptamers into acyclovir-controllable antagonists against physiologic target proteins.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1827-1838.e7"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078687","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 : 2024-10-17DOI: 10.1016/j.chembiol.2024.05.003
Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) have important regulatory roles in energy metabolism, yet their specific functions and underlying regulatory mechanisms have not been delineated. Using a chemical-genetic screening strategy, we demonstrated that the JAK/STAT3 pathway is the primary regulatory mechanism governing mtDNA G4 dynamics in hypoxic cancer cells. Further proteomic analysis showed that activation of the JAK/STAT3 pathway facilitates the translocation of RelA, a member of the NF-κB family, to the mitochondria, where RelA binds to mtDNA G4s and promotes their folding, resulting in increased mtDNA instability, inhibited mtDNA transcription, and subsequent mitochondrial dysfunction. This binding event disrupts the equilibrium of energy metabolism, catalyzing a metabolic shift favoring glycolysis. Collectively, the results provide insights into a strategy employed by cancer cells to adapt to hypoxia through metabolic reprogramming.
{"title":"Mitochondrial RelA empowers mtDNA G-quadruplex formation for hypoxia adaptation in cancer cells","authors":"","doi":"10.1016/j.chembiol.2024.05.003","DOIUrl":"10.1016/j.chembiol.2024.05.003","url":null,"abstract":"<div><div>Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) have important regulatory roles in energy metabolism, yet their specific functions and underlying regulatory mechanisms have not been delineated. Using a chemical-genetic screening strategy, we demonstrated that the JAK/STAT3 pathway is the primary regulatory mechanism governing mtDNA G4 dynamics in hypoxic cancer cells. Further proteomic<span><span> analysis showed that activation of the JAK/STAT3 pathway facilitates the translocation of RelA, a member of the NF-κB family, to the mitochondria, where RelA binds to mtDNA G4s and promotes their folding, resulting in increased mtDNA instability, inhibited mtDNA transcription, and subsequent mitochondrial dysfunction. This binding event disrupts the equilibrium of energy metabolism, catalyzing a metabolic shift favoring glycolysis. Collectively, the results provide insights into a strategy employed by cancer cells to adapt to </span>hypoxia through metabolic reprogramming.</span></div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1800-1814.e7"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177880","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 : 2024-10-17DOI: 10.1016/j.chembiol.2024.09.001
Beste Mutlu , Kfir Sharabi , Jee Hyung Sohn , Bo Yuan , Pedro Latorre-Muro , Xin Qin , Jin-Seon Yook , Hua Lin , Deyang Yu , João Paulo G. Camporez , Shingo Kajimura , Gerald I. Shulman , Sheng Hui , Theodore M. Kamenecka , Patrick R. Griffin , Pere Puigserver
Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules.
{"title":"Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation","authors":"Beste Mutlu , Kfir Sharabi , Jee Hyung Sohn , Bo Yuan , Pedro Latorre-Muro , Xin Qin , Jin-Seon Yook , Hua Lin , Deyang Yu , João Paulo G. Camporez , Shingo Kajimura , Gerald I. Shulman , Sheng Hui , Theodore M. Kamenecka , Patrick R. Griffin , Pere Puigserver","doi":"10.1016/j.chembiol.2024.09.001","DOIUrl":"10.1016/j.chembiol.2024.09.001","url":null,"abstract":"<div><div>Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1772-1786.e5"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325634","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 : 2024-10-17DOI: 10.1016/j.chembiol.2024.06.002
Spread of antimicrobial resistances urges a need for new drugs against Mycobacterium tuberculosis (Mtb) with mechanisms differing from current antibiotics. Previously, callyaerins were identified as promising anti-tubercular agents, representing a class of hydrophobic cyclopeptides with an unusual (Z)-2,3-di-aminoacrylamide unit. Here, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of structural determinants relevant for antibacterial activity. Callyaerins are bacteriostatics selectively active against Mtb, including extensively drug-resistant strains, with minimal cytotoxicity against human cells and promising intracellular activity. By combining mutant screens and various chemical proteomics approaches, we showed that callyaerins target the non-essential, Mtb-specific membrane protein Rv2113, triggering a complex dysregulation of the proteome, characterized by global downregulation of lipid biosynthesis, cell division, DNA repair, and replication. Our study thus identifies Rv2113 as a previously undescribed Mtb-specific drug target and demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs.
{"title":"The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113","authors":"","doi":"10.1016/j.chembiol.2024.06.002","DOIUrl":"10.1016/j.chembiol.2024.06.002","url":null,"abstract":"<div><div>Spread of antimicrobial resistances urges a need for new drugs against <em>Mycobacterium tuberculosis</em> (Mtb) with mechanisms differing from current antibiotics. Previously, callyaerins were identified as promising anti-tubercular agents, representing a class of hydrophobic cyclopeptides with an unusual (<em>Z</em>)-2,3-di-aminoacrylamide unit. Here, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of structural determinants relevant for antibacterial activity. Callyaerins are bacteriostatics selectively active against Mtb, including extensively drug-resistant strains, with minimal cytotoxicity against human cells and promising intracellular activity. By combining mutant screens and various chemical proteomics approaches, we showed that callyaerins target the non-essential, Mtb-specific membrane protein Rv2113, triggering a complex dysregulation of the proteome, characterized by global downregulation of lipid biosynthesis, cell division, DNA repair, and replication. Our study thus identifies Rv2113 as a previously undescribed Mtb-specific drug target and demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1755-1771.e73"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561721","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 : 2024-10-17DOI: 10.1016/j.chembiol.2024.06.016
Sophia X. Tang , Christina M. Camara , Joy A. Franco , Maria F. Pazyra-Murphy , Yihang Li , Marina Godes , Benjamin M. Moyer , Gregory H. Bird , Rosalind A. Segal , Loren D. Walensky
BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining “staple” and alanine scanning approaches with molecular dynamics simulations. We generated and identified stapled BCL-w BH4 peptides with optimized IP3 receptor binding and neuroprotective activities. Point mutagenesis further revealed the sequence determinants for BCL-w BH4 specificity, providing a blueprint for therapeutic targeting of IP3 receptors to achieve neuroprotection.
{"title":"Dissecting the neuroprotective interaction between the BH4 domain of BCL-w and the IP3 receptor","authors":"Sophia X. Tang , Christina M. Camara , Joy A. Franco , Maria F. Pazyra-Murphy , Yihang Li , Marina Godes , Benjamin M. Moyer , Gregory H. Bird , Rosalind A. Segal , Loren D. Walensky","doi":"10.1016/j.chembiol.2024.06.016","DOIUrl":"10.1016/j.chembiol.2024.06.016","url":null,"abstract":"<div><div>BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining “staple” and alanine scanning approaches with molecular dynamics simulations. We generated and identified stapled BCL-w BH4 peptides with optimized IP3 receptor binding and neuroprotective activities. Point mutagenesis further revealed the sequence determinants for BCL-w BH4 specificity, providing a blueprint for therapeutic targeting of IP3 receptors to achieve neuroprotection.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1815-1826.e5"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141769251","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 : 2024-10-17DOI: 10.1016/j.chembiol.2024.08.001
Hao Ye , Guangyu Luo , Zhenwu Zheng , Xiaofang Li , Jie Cao , Jia Liu , Junbiao Dai
Yeast has been extensively studied and engineered due to its genetic amenability. Projects like Sc2.0 and Sc3.0 have demonstrated the feasibility of constructing synthetic yeast genomes, yielding promising results in both research and industrial applications. In contrast, plant synthetic genomics has faced challenges due to the complexity of plant genomes. However, recent advancements of the project SynMoss, utilizing the model moss plant Physcomitrium patens, offer opportunities for plant synthetic genomics. The shared characteristics between P. patens and yeast, such as high homologous recombination rates and dominant haploid life cycle, enable researchers to manipulate P. patens genomes similarly, opening promising avenues for research and application in plant synthetic biology. In conclusion, harnessing insights from yeast synthetic genomics and applying them to plants, with P. patens as a breakthrough, shows great potential for revolutionizing plant synthetic genomics.
{"title":"Plant synthetic genomics: Big lessons from the little yeast","authors":"Hao Ye , Guangyu Luo , Zhenwu Zheng , Xiaofang Li , Jie Cao , Jia Liu , Junbiao Dai","doi":"10.1016/j.chembiol.2024.08.001","DOIUrl":"10.1016/j.chembiol.2024.08.001","url":null,"abstract":"<div><div>Yeast has been extensively studied and engineered due to its genetic amenability. Projects like Sc2.0 and Sc3.0 have demonstrated the feasibility of constructing synthetic yeast genomes, yielding promising results in both research and industrial applications. In contrast, plant synthetic genomics has faced challenges due to the complexity of plant genomes. However, recent advancements of the project SynMoss, utilizing the model moss plant <em>Physcomitrium patens</em>, offer opportunities for plant synthetic genomics. The shared characteristics between <em>P. patens</em> and yeast, such as high homologous recombination rates and dominant haploid life cycle, enable researchers to manipulate <em>P. patens</em> genomes similarly, opening promising avenues for research and application in plant synthetic biology. In conclusion, harnessing insights from yeast synthetic genomics and applying them to plants, with <em>P. patens</em> as a breakthrough, shows great potential for revolutionizing plant synthetic genomics.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1745-1754"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090534","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}
A photocatalytic click chemistry approach, offering a significant advancement over conventional methods in RNA function modulation is described. This innovative method, utilizing light-activated small molecules, provides a high level of precision and control in RNA regulation, particularly effective in intricate cellular processes. By applying this strategy to CRISPR-Cas9 gene editing, we demonstrate its effectiveness in enhancing gene editing specificity and markedly reducing off-target effects. Our approach employs a vinyl ether modification in RNA, which activated under visible light with a phenanthrenequinone derivative, creating a CRISPR-OFF switch that precisely regulates CRISPR system activity. This method not only represents an advancement in genomic interventions but also offers broad applications in gene regulation, paving the way for safer and more reliable gene editing in therapeutic genomics.
{"title":"Reducing CRISPR-Cas9 off-target effects by optically controlled chemical modifications of guide RNA","authors":"Qianqian Qi , Xingyu Liu , Wei Xiong , Kaisong Zhang , Wei Shen , Yuanyuan Zhang , Xinyan Xu , Cheng Zhong , Yan Zhang , Tian Tian , Xiang Zhou","doi":"10.1016/j.chembiol.2024.09.006","DOIUrl":"10.1016/j.chembiol.2024.09.006","url":null,"abstract":"<div><div>A photocatalytic click chemistry approach, offering a significant advancement over conventional methods in RNA function modulation is described. This innovative method, utilizing light-activated small molecules, provides a high level of precision and control in RNA regulation, particularly effective in intricate cellular processes. By applying this strategy to CRISPR-Cas9 gene editing, we demonstrate its effectiveness in enhancing gene editing specificity and markedly reducing off-target effects. Our approach employs a vinyl ether modification in RNA, which activated under visible light with a phenanthrenequinone derivative, creating a CRISPR-OFF switch that precisely regulates CRISPR system activity. This method not only represents an advancement in genomic interventions but also offers broad applications in gene regulation, paving the way for safer and more reliable gene editing in therapeutic genomics.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1839-1851.e8"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384832","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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