Pub Date : 2024-06-29DOI: 10.1038/s42004-024-01224-0
Minh Sai, Emily C. Hank, Hin-Man Tai, Till Kasch, Max Lewandowski, Michelle Vincendeau, Julian A. Marschner, Daniel Merk
The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson’s and Alzheimer’s disease as well as multiple sclerosis but high-quality chemical tools for pharmacological target validation of Nurr1 are rare. We have employed the weak Nurr1 modulator amodiaquine (AQ) and AQ-derived fragments as templates to design a new Nurr1 agonist chemotype by scaffold hopping and fragment growing strategies. Systematic structural optimization of this scaffold yielded Nurr1 agonists with nanomolar potency and binding affinity. Comprehensive in vitro profiling revealed efficient cellular target engagement and compliance with the highest probe criteria. In human midbrain organoids bearing a Parkinson-driving LRRK2 mutation, a novel Nurr1 agonist rescued tyrosine hydroxylase expression highlighting the potential of the new Nurr1 modulator chemotype as lead and as a chemical tool for biological studies. Nuclear receptor-related 1 (Nurr1) is a promising candidate target for neurodegenerative disease treatment, however, the validation of their therapeutic potential remains underexplored due to a lack of high-quality chemical tools. Here, the authors develop Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing, exhibiting nanomolar potency and efficient cellular target engagement, showing their potential as lead and chemical tools.
{"title":"Development of Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing","authors":"Minh Sai, Emily C. Hank, Hin-Man Tai, Till Kasch, Max Lewandowski, Michelle Vincendeau, Julian A. Marschner, Daniel Merk","doi":"10.1038/s42004-024-01224-0","DOIUrl":"10.1038/s42004-024-01224-0","url":null,"abstract":"The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson’s and Alzheimer’s disease as well as multiple sclerosis but high-quality chemical tools for pharmacological target validation of Nurr1 are rare. We have employed the weak Nurr1 modulator amodiaquine (AQ) and AQ-derived fragments as templates to design a new Nurr1 agonist chemotype by scaffold hopping and fragment growing strategies. Systematic structural optimization of this scaffold yielded Nurr1 agonists with nanomolar potency and binding affinity. Comprehensive in vitro profiling revealed efficient cellular target engagement and compliance with the highest probe criteria. In human midbrain organoids bearing a Parkinson-driving LRRK2 mutation, a novel Nurr1 agonist rescued tyrosine hydroxylase expression highlighting the potential of the new Nurr1 modulator chemotype as lead and as a chemical tool for biological studies. Nuclear receptor-related 1 (Nurr1) is a promising candidate target for neurodegenerative disease treatment, however, the validation of their therapeutic potential remains underexplored due to a lack of high-quality chemical tools. Here, the authors develop Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing, exhibiting nanomolar potency and efficient cellular target engagement, showing their potential as lead and chemical tools.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11217349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-28DOI: 10.1038/s42004-024-01229-9
Thijs W. van Veldhuisen, Madelief A. M. Verwiel, Sebastian Novosedlik, Luc Brunsveld, Jan C. M. van Hest
Living cells can modulate their response to environmental cues by changing their sensitivities for molecular signals. Artificial cells are promising model platforms to study intercellular communication, but populations with such differentiated behavior remain underexplored. Here, we show the affinity-regulated exchange of proteins in distinct populations of coacervate-based artificial cells via protein-protein interactions (PPI) of the hub protein 14-3-3. By loading different coacervates with different isoforms of 14-3-3, featuring varying PPI affinities, a client peptide is directed to the more strongly recruiting coacervates. By switching affinity of client proteins through phosphorylation, weaker binding partners can be outcompeted for their 14-3-3 binding, inducing their release from artificial cells. Combined, a communication system between coacervates is constructed, which leads to the transport of client proteins from strongly recruiting coacervates to weakly recruiting ones. The results demonstrate that affinity engineering and competitive binding can provide directed protein uptake and exchange between artificial cells. Artificial cells are promising models to study intercellular communications, however, the chemical communication between populations of artificial cells remains underexplored. Here, the authors show the exchange of proteins between distinct populations of coacervate-based artificial cells by regulation of protein affinity and competitive binding with hub protein 14-3-3.
活细胞可以通过改变对分子信号的敏感度来调节对环境线索的反应。人工细胞是研究细胞间通讯的理想模型平台，但具有这种分化行为的群体仍未得到充分探索。在这里，我们通过枢纽蛋白14-3-3的蛋白质-蛋白质相互作用（PPI），展示了基于共凝胶的人工细胞不同群体中蛋白质的亲和调节交换。通过用具有不同 PPI 亲和力的 14-3-3 的不同异构体装载不同的共沉淀，客户肽就会被引导到招募作用更强的共沉淀上。通过磷酸化改变客户蛋白的亲和力，较弱的结合伙伴就能在与 14-3-3 结合的竞争中胜出，从而诱导它们从人工细胞中释放出来。此外，还构建了一个凝聚体之间的交流系统，从而将客户蛋白从强吸附凝聚体转运到弱吸附凝聚体。研究结果表明，亲和力工程和竞争性结合可以在人工细胞之间提供定向蛋白质吸收和交换。
{"title":"Competitive protein recruitment in artificial cells","authors":"Thijs W. van Veldhuisen, Madelief A. M. Verwiel, Sebastian Novosedlik, Luc Brunsveld, Jan C. M. van Hest","doi":"10.1038/s42004-024-01229-9","DOIUrl":"10.1038/s42004-024-01229-9","url":null,"abstract":"Living cells can modulate their response to environmental cues by changing their sensitivities for molecular signals. Artificial cells are promising model platforms to study intercellular communication, but populations with such differentiated behavior remain underexplored. Here, we show the affinity-regulated exchange of proteins in distinct populations of coacervate-based artificial cells via protein-protein interactions (PPI) of the hub protein 14-3-3. By loading different coacervates with different isoforms of 14-3-3, featuring varying PPI affinities, a client peptide is directed to the more strongly recruiting coacervates. By switching affinity of client proteins through phosphorylation, weaker binding partners can be outcompeted for their 14-3-3 binding, inducing their release from artificial cells. Combined, a communication system between coacervates is constructed, which leads to the transport of client proteins from strongly recruiting coacervates to weakly recruiting ones. The results demonstrate that affinity engineering and competitive binding can provide directed protein uptake and exchange between artificial cells. Artificial cells are promising models to study intercellular communications, however, the chemical communication between populations of artificial cells remains underexplored. Here, the authors show the exchange of proteins between distinct populations of coacervate-based artificial cells by regulation of protein affinity and competitive binding with hub protein 14-3-3.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-28DOI: 10.1038/s42004-024-01228-w
Sihyeong Yi, Ji Hyae Lee, Hana Cho, Kannan Vaithegi, Dawon Yi, Sijun Noh, Seung Bum Park
Pyridine, an essential structure in drug development, shows a wide array of bioactivities according to its substitution patterns. Among the bioactive pyridines, meta-substituted pyridines suffer from limited synthetic approaches despite their significance. In this study, we present a condensation-based synthetic method enabling the facile incorporation of biologically relevant functional groups at the meta position of pyridine. This methodology unveiled the concealed reactivity of 3-formyl(aza)indoles as diformylmethane analogs for synthesizing dissymmetric di-meta-substituted pyridines without ortho and para substitutions. Furthermore, we uncovered resonance-assisted hydrogen bonding (RAHB) as the requirement for the in situ generation of enamines, the key intermediates of this transformation. Successful development of the designed methodology linked to wide applications—core remodeling of natural products, drug–natural product conjugation, late-stage functionalization of drug molecules, and synthesis of the regioisomeric CZC24832. Furthermore, we discovered anti-inflammatory agents through the functional evaluation of synthesized bi-heteroaryl analogs, signifying the utility of this methodology. Pyridine is an essential structural motif in medicinal chemistry and shows a wide range of bioactivities based on its substitution patterns, however, the meta-substitution of pyridine remains challenging. Here, the authors develop the synthesis of dissymmetric di-meta-substituted pyridines from 3-formyl(aza)indoles through the in situ generation of enamines via resonance-assisted hydrogen bonding, showcasing various synthetic applications in medicinal chemistry.
{"title":"Unveiled reactivity of masked diformylmethane with enamines forming resonance-assisted hydrogen bonding leads to di-meta-substituted pyridines","authors":"Sihyeong Yi, Ji Hyae Lee, Hana Cho, Kannan Vaithegi, Dawon Yi, Sijun Noh, Seung Bum Park","doi":"10.1038/s42004-024-01228-w","DOIUrl":"10.1038/s42004-024-01228-w","url":null,"abstract":"Pyridine, an essential structure in drug development, shows a wide array of bioactivities according to its substitution patterns. Among the bioactive pyridines, meta-substituted pyridines suffer from limited synthetic approaches despite their significance. In this study, we present a condensation-based synthetic method enabling the facile incorporation of biologically relevant functional groups at the meta position of pyridine. This methodology unveiled the concealed reactivity of 3-formyl(aza)indoles as diformylmethane analogs for synthesizing dissymmetric di-meta-substituted pyridines without ortho and para substitutions. Furthermore, we uncovered resonance-assisted hydrogen bonding (RAHB) as the requirement for the in situ generation of enamines, the key intermediates of this transformation. Successful development of the designed methodology linked to wide applications—core remodeling of natural products, drug–natural product conjugation, late-stage functionalization of drug molecules, and synthesis of the regioisomeric CZC24832. Furthermore, we discovered anti-inflammatory agents through the functional evaluation of synthesized bi-heteroaryl analogs, signifying the utility of this methodology. Pyridine is an essential structural motif in medicinal chemistry and shows a wide range of bioactivities based on its substitution patterns, however, the meta-substitution of pyridine remains challenging. Here, the authors develop the synthesis of dissymmetric di-meta-substituted pyridines from 3-formyl(aza)indoles through the in situ generation of enamines via resonance-assisted hydrogen bonding, showcasing various synthetic applications in medicinal chemistry.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-28DOI: 10.1038/s42004-024-01231-1
Tuo Li, Annika J. E. Borg, Leo Krammer, Hansjörg Weber, Rolf Breinbauer, Bernd Nidetzky
Glycosylated derivatives of natural product polyphenols display a spectrum of biological activities, rendering them critical for both nutritional and pharmacological applications. Their enzymatic synthesis by glycosyltransferases is frequently constrained by the limited repertoire of characterized enzyme-catalyzed transformations. Here, we explore the glycosylation capabilities and substrate preferences of newly identified plant uridine diphosphate (UDP)-dependent glycosyltransferases (UGTs) within the UGT72 and UGT84 families, with particular focus on natural polyphenol glycosylation from UDP-glucose. Four UGTs are classified according to their phylogenetic relationships and reaction products, identifying them as biocatalysts for either glucoside (UGT72 enzymes) or glucose ester (UGT84 members) formation from selected phenylpropanoid compounds. Detailed kinetic evaluations expose the unique attributes of these enzymes, including their specific activities and regio-selectivities towards diverse polyphenolic substrates, with product characterizations validating the capacity of UGT84 family members to perform di-O-glycosylation on flavones. Sequence analysis coupled with structural predictions through AlphaFold reveal an unexpected absence of a conserved threonine residue across all four enzymes, a trait previously linked to pentosyltransferases. This comparative analysis broadens the understood substrate specificity range for UGT72 and UGT84 enzymes, enhancing our understanding of their utility in the production of natural phenolic glycosides. The findings from this in-depth characterization provide valuable insights into the functional versatility of UGT-mediated reactions. Uridine diphosphate-dependent glycosyltransferases (UGTs) play a vital role in the biocatalytic glycosylation of phenolic compounds, however, UGT-catalyzed transformations remain not well-characterized. Here, the authors investigate new members of UGT72 and UGT84 families, revealing their specific reactivity and regio-selectivity on selected polyphenolic substrates.
{"title":"Discovery, characterization, and comparative analysis of new UGT72 and UGT84 family glycosyltransferases","authors":"Tuo Li, Annika J. E. Borg, Leo Krammer, Hansjörg Weber, Rolf Breinbauer, Bernd Nidetzky","doi":"10.1038/s42004-024-01231-1","DOIUrl":"10.1038/s42004-024-01231-1","url":null,"abstract":"Glycosylated derivatives of natural product polyphenols display a spectrum of biological activities, rendering them critical for both nutritional and pharmacological applications. Their enzymatic synthesis by glycosyltransferases is frequently constrained by the limited repertoire of characterized enzyme-catalyzed transformations. Here, we explore the glycosylation capabilities and substrate preferences of newly identified plant uridine diphosphate (UDP)-dependent glycosyltransferases (UGTs) within the UGT72 and UGT84 families, with particular focus on natural polyphenol glycosylation from UDP-glucose. Four UGTs are classified according to their phylogenetic relationships and reaction products, identifying them as biocatalysts for either glucoside (UGT72 enzymes) or glucose ester (UGT84 members) formation from selected phenylpropanoid compounds. Detailed kinetic evaluations expose the unique attributes of these enzymes, including their specific activities and regio-selectivities towards diverse polyphenolic substrates, with product characterizations validating the capacity of UGT84 family members to perform di-O-glycosylation on flavones. Sequence analysis coupled with structural predictions through AlphaFold reveal an unexpected absence of a conserved threonine residue across all four enzymes, a trait previously linked to pentosyltransferases. This comparative analysis broadens the understood substrate specificity range for UGT72 and UGT84 enzymes, enhancing our understanding of their utility in the production of natural phenolic glycosides. The findings from this in-depth characterization provide valuable insights into the functional versatility of UGT-mediated reactions. Uridine diphosphate-dependent glycosyltransferases (UGTs) play a vital role in the biocatalytic glycosylation of phenolic compounds, however, UGT-catalyzed transformations remain not well-characterized. Here, the authors investigate new members of UGT72 and UGT84 families, revealing their specific reactivity and regio-selectivity on selected polyphenolic substrates.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-27DOI: 10.1038/s42004-024-01227-x
Nicole Trainor, Harry J. Whitwell, Beatriz Jiménez, Katie Addison, Emily Leonidou, Peter A. DiMaggio, Matthew J. Fuchter
Epigenetic processes influence health and disease through mechanisms which alter gene expression. In contrast to genetic changes which affect DNA sequences, epigenetic marks include DNA base modifications or post-translational modification (PTM) of proteins. Histone methylation is a prominent and versatile example of an epigenetic marker: gene expression or silencing is dependent on the location and extent of the methylation. Protein methyltransferases exhibit functional redundancy and broad preferences for multiple histone residues, which presents a challenge for the study of their individual activities. We developed an isotopically labelled analogue of co-factor S-adenosyl-L-methionine (13CD3-BrSAM), with selectivity for the histone lysine methyltransferase DOT1L, permitting tracking of methylation activity by mass spectrometry (MS). This concept could be applied to other methyltransferases, linking PTM discovery to enzymatic mediators. Histone methylation by histone lysine methyltransferases (HKMTs) is a vital post-translational modification regulating gene expression, however, selective mapping of methylation by proteomics analysis remains challenging. Here, the authors develop a heavy co-factor analogue 13CD3-BrSAM for HKMT DOT1L that can selectively heavy label target substrates, and map their methylation by proteomics.
表观遗传过程通过改变基因表达的机制影响健康和疾病。与影响 DNA 序列的基因变化不同，表观遗传标记包括 DNA 碱基修饰或蛋白质翻译后修饰（PTM）。组蛋白甲基化是表观遗传标记的一个突出和多用途的例子：基因表达或沉默取决于甲基化的位置和程度。蛋白甲基转移酶对多个组蛋白残基表现出功能冗余和广泛的偏好，这给研究它们的个体活性带来了挑战。我们开发了一种同位素标记的辅助因子 S-腺苷-L-蛋氨酸类似物（13CD3-BrSAM），它对组蛋白赖氨酸甲基转移酶 DOT1L 具有选择性，可通过质谱（MS）追踪甲基化活性。这一概念可应用于其他甲基转移酶，将 PTM 的发现与酶介质联系起来。
{"title":"Tracking DOT1L methyltransferase activity by stable isotope labelling using a selective synthetic co-factor","authors":"Nicole Trainor, Harry J. Whitwell, Beatriz Jiménez, Katie Addison, Emily Leonidou, Peter A. DiMaggio, Matthew J. Fuchter","doi":"10.1038/s42004-024-01227-x","DOIUrl":"10.1038/s42004-024-01227-x","url":null,"abstract":"Epigenetic processes influence health and disease through mechanisms which alter gene expression. In contrast to genetic changes which affect DNA sequences, epigenetic marks include DNA base modifications or post-translational modification (PTM) of proteins. Histone methylation is a prominent and versatile example of an epigenetic marker: gene expression or silencing is dependent on the location and extent of the methylation. Protein methyltransferases exhibit functional redundancy and broad preferences for multiple histone residues, which presents a challenge for the study of their individual activities. We developed an isotopically labelled analogue of co-factor S-adenosyl-L-methionine (13CD3-BrSAM), with selectivity for the histone lysine methyltransferase DOT1L, permitting tracking of methylation activity by mass spectrometry (MS). This concept could be applied to other methyltransferases, linking PTM discovery to enzymatic mediators. Histone methylation by histone lysine methyltransferases (HKMTs) is a vital post-translational modification regulating gene expression, however, selective mapping of methylation by proteomics analysis remains challenging. Here, the authors develop a heavy co-factor analogue 13CD3-BrSAM for HKMT DOT1L that can selectively heavy label target substrates, and map their methylation by proteomics.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-27DOI: 10.1038/s42004-024-01230-2
Gongli Cai, Yishu Bao, Qingyun Li, Pang-Hung Hsu, Jiang Xia, Jacky Chi Ki Ngo
Serine–arginine (SR) proteins are splicing factors that play essential roles in both constitutive and alternative pre-mRNA splicing. Phosphorylation of their C-terminal RS domains by SR protein kinases (SRPKs) regulates their localization and diverse cellular activities. Dysregulation of phosphorylation has been implicated in many human diseases, including cancers. Here, we report the development of a covalent protein–protein interaction inhibitor, C-DBS, that targets a lysine residue within the SRPK-specific docking groove to block the interaction and phosphorylation of the prototypic SR protein SRSF1. C-DBS exhibits high specificity and conjugation efficiency both in vitro and in cellulo. This self-cell-penetrating inhibitor attenuates the phosphorylation of endogenous SR proteins and subsequently inhibits the angiogenesis, migration, and invasion of cancer cells. These findings provide a new foundation for the development of covalent SRPK inhibitors for combatting diseases such as cancer and viral infections and overcoming the resistance encountered by ATP-competitive inhibitors. The binding and phosphorylation of serine–arginine-rich (SR) proteins by SR protein kinases (SRPKs) is essential to regulate target gene expression, however, the efficient inhibition of this interaction and phosphorylation remains underexplored. Here, the authors develop a covalent inhibitor that targets the lysine residue within the SRPK-specific docking groove, to block interaction and phosphorylation of the prototypic SR protein SRSF1.
丝氨酸-精氨酸（SR）蛋白是一种剪接因子，在组成型和替代型前 mRNA 剪接中发挥着重要作用。丝氨酸精氨酸（SR）蛋白激酶（SRPKs）对其 C 端 RS 结构域进行磷酸化，从而调节其定位和多种细胞活动。磷酸化失调与包括癌症在内的多种人类疾病有关。在这里，我们报告了一种共价蛋白质-蛋白质相互作用抑制剂 C-DBS的开发情况，它以SRPK特异性对接沟槽中的一个赖氨酸残基为靶点，阻断原型SR蛋白SRSF1的相互作用和磷酸化。C-DBS 在体外和细胞内都表现出高度的特异性和结合效率。这种自细胞穿透抑制剂可抑制内源性 SR 蛋白的磷酸化，进而抑制癌细胞的血管生成、迁移和侵袭。这些发现为开发共价 SRPK 抑制剂以防治癌症和病毒感染等疾病以及克服 ATP 竞争性抑制剂的抗药性奠定了新的基础。
{"title":"Design of a covalent protein-protein interaction inhibitor of SRPKs to suppress angiogenesis and invasion of cancer cells","authors":"Gongli Cai, Yishu Bao, Qingyun Li, Pang-Hung Hsu, Jiang Xia, Jacky Chi Ki Ngo","doi":"10.1038/s42004-024-01230-2","DOIUrl":"10.1038/s42004-024-01230-2","url":null,"abstract":"Serine–arginine (SR) proteins are splicing factors that play essential roles in both constitutive and alternative pre-mRNA splicing. Phosphorylation of their C-terminal RS domains by SR protein kinases (SRPKs) regulates their localization and diverse cellular activities. Dysregulation of phosphorylation has been implicated in many human diseases, including cancers. Here, we report the development of a covalent protein–protein interaction inhibitor, C-DBS, that targets a lysine residue within the SRPK-specific docking groove to block the interaction and phosphorylation of the prototypic SR protein SRSF1. C-DBS exhibits high specificity and conjugation efficiency both in vitro and in cellulo. This self-cell-penetrating inhibitor attenuates the phosphorylation of endogenous SR proteins and subsequently inhibits the angiogenesis, migration, and invasion of cancer cells. These findings provide a new foundation for the development of covalent SRPK inhibitors for combatting diseases such as cancer and viral infections and overcoming the resistance encountered by ATP-competitive inhibitors. The binding and phosphorylation of serine–arginine-rich (SR) proteins by SR protein kinases (SRPKs) is essential to regulate target gene expression, however, the efficient inhibition of this interaction and phosphorylation remains underexplored. Here, the authors develop a covalent inhibitor that targets the lysine residue within the SRPK-specific docking groove, to block interaction and phosphorylation of the prototypic SR protein SRSF1.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-27DOI: 10.1038/s42004-024-01232-0
Sven Ullrich, Upamali Somathilake, Minghao Shang, Christoph Nitsche
Genetically encoded libraries play a crucial role in discovering structurally rigid, high-affinity macrocyclic peptide ligands for therapeutic applications. Bicyclic peptides with metal centres like bismuth were recently developed as a new type of constrained peptide with notable affinity, stability and membrane permeability. This study represents the genetic encoding of peptide-bismuth and peptide-arsenic bicycles in phage display. We introduce bismuth tripotassium dicitrate (gastrodenol) as a water-soluble bismuth(III) reagent for phage library modification and in situ bicyclic peptide preparation, eliminating the need for organic co-solvents. Additionally, we explore arsenic(III) as an alternative thiophilic element that is used analogously to our previously introduced bicyclic peptides with a bismuth core. The modification of phage libraries and peptides with these elements is instantaneous and entirely biocompatible, offering an advantage over conventional alkylation-based methods. In a pilot display screening campaign aimed at identifying ligands for the biotin-binding protein streptavidin, we demonstrate the enrichment of bicyclic peptides with dissociation constants two orders of magnitude lower than those of their linear counterparts, underscoring the impact of structural constraint on binding affinity. Genetically encoded libraries are key technologies in peptide drug discovery, and the constraint of peptide structures by macrocyclization is known to improve their therapeutic properties. Here, the authors report biocompatible bismuth and arsenic bicyclization of genetically encoded peptide libraries displayed on phages. The resulting bicycles show improved binding affinity over their linear counterparts.
{"title":"Phage-encoded bismuth bicycles enable instant access to targeted bioactive peptides","authors":"Sven Ullrich, Upamali Somathilake, Minghao Shang, Christoph Nitsche","doi":"10.1038/s42004-024-01232-0","DOIUrl":"10.1038/s42004-024-01232-0","url":null,"abstract":"Genetically encoded libraries play a crucial role in discovering structurally rigid, high-affinity macrocyclic peptide ligands for therapeutic applications. Bicyclic peptides with metal centres like bismuth were recently developed as a new type of constrained peptide with notable affinity, stability and membrane permeability. This study represents the genetic encoding of peptide-bismuth and peptide-arsenic bicycles in phage display. We introduce bismuth tripotassium dicitrate (gastrodenol) as a water-soluble bismuth(III) reagent for phage library modification and in situ bicyclic peptide preparation, eliminating the need for organic co-solvents. Additionally, we explore arsenic(III) as an alternative thiophilic element that is used analogously to our previously introduced bicyclic peptides with a bismuth core. The modification of phage libraries and peptides with these elements is instantaneous and entirely biocompatible, offering an advantage over conventional alkylation-based methods. In a pilot display screening campaign aimed at identifying ligands for the biotin-binding protein streptavidin, we demonstrate the enrichment of bicyclic peptides with dissociation constants two orders of magnitude lower than those of their linear counterparts, underscoring the impact of structural constraint on binding affinity. Genetically encoded libraries are key technologies in peptide drug discovery, and the constraint of peptide structures by macrocyclization is known to improve their therapeutic properties. Here, the authors report biocompatible bismuth and arsenic bicyclization of genetically encoded peptide libraries displayed on phages. The resulting bicycles show improved binding affinity over their linear counterparts.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Building stimuli-responsive supramolecular systems is a way for chemists to achieve spatio-temporal control over complex systems as well as a promising strategy for applications ranging from sensing to drug-delivery. For its large spectrum of biological and biomedical implications, adenosine 5’-triphosphate (ATP) is a particularly interesting target for such a purpose but photoresponsive ATP-based systems have mainly been relying on covalent modification of ATP. Here, we show that simply mixing ATP with AzoDiGua, an azobenzene-guanidium compound with photodependent nucleotide binding affinity, results in the spontaneous self-assembly of the two non-fluorescent compounds into photoreversible, micrometer-sized and fluorescent aggregates. Obtained in water at room temperature and physiological pH, these supramolecular structures are dynamic and respond to several chemical, physical and biological stimuli. The presence of azobenzene allows a fast and photoreversible control of their assembly. ATP chelating properties to metal dications enable ion-triggered disassembly and fluorescence control with valence-selectivity. Finally, the supramolecular aggregates are disassembled by alkaline phosphatase in a few minutes at room temperature, resulting in enzymatic control of fluorescence. These results highlight the interest of using a photoswitchable nucleotide binding partner as a self-assembly brick to build highly responsive supramolecular entities involving biological targets without the need to covalently modify them. Building stimuli-responsive supramolecular materials enables spatiotemporal control over complex systems, and is a promising strategy for a range of applications. Here, mixing adenosine 5’-triphosphate (ATP) with an azobenzene-guanidium compound possessing photodependent nucleotide binding affinity is shown to result in the spontaneous photo-reversible self-assembly of these compounds into micrometer-sized fluorescent aggregates that display dynamic responses to several chemical, physical and biological stimuli.
建立刺激响应型超分子系统是化学家实现复杂系统时空控制的一种方法，也是一种应用前景广阔的策略，应用范围从传感到药物输送。腺苷-5'-三磷酸（ATP）具有广泛的生物和生物医学意义，是一个特别有趣的目标，但基于 ATP 的光致反应系统主要依赖于对 ATP 的共价修饰。在这里，我们展示了只需将 ATP 与偶氮二胍（一种具有光依赖性核苷酸结合亲和力的偶氮苯胍化合物）混合，这两种非荧光化合物就能自发地自组装成光可逆的、微米大小的荧光聚集体。这些超分子结构在室温和生理 pH 值条件下的水中形成，具有活力，能对多种化学、物理和生物刺激做出反应。偶氮苯的存在可以快速、光可逆地控制它们的组装。ATP 与金属二价的螯合特性使离子触发的解体和具有价选择性的荧光控制成为可能。最后，碱性磷酸酶可在室温下几分钟内分解超分子聚集体，从而实现对荧光的酶控。这些结果凸显了使用可光电开关的核苷酸结合伙伴作为自组装砖来构建涉及生物靶标的高响应超分子实体的兴趣，而无需对其进行共价修饰。
{"title":"ATP/azobenzene-guanidinium self-assembly into fluorescent and multi-stimuli-responsive supramolecular aggregates","authors":"Olivier Abodja, Nadia Touati, Mathieu Morel, Sergii Rudiuk, Damien Baigl","doi":"10.1038/s42004-024-01226-y","DOIUrl":"10.1038/s42004-024-01226-y","url":null,"abstract":"Building stimuli-responsive supramolecular systems is a way for chemists to achieve spatio-temporal control over complex systems as well as a promising strategy for applications ranging from sensing to drug-delivery. For its large spectrum of biological and biomedical implications, adenosine 5’-triphosphate (ATP) is a particularly interesting target for such a purpose but photoresponsive ATP-based systems have mainly been relying on covalent modification of ATP. Here, we show that simply mixing ATP with AzoDiGua, an azobenzene-guanidium compound with photodependent nucleotide binding affinity, results in the spontaneous self-assembly of the two non-fluorescent compounds into photoreversible, micrometer-sized and fluorescent aggregates. Obtained in water at room temperature and physiological pH, these supramolecular structures are dynamic and respond to several chemical, physical and biological stimuli. The presence of azobenzene allows a fast and photoreversible control of their assembly. ATP chelating properties to metal dications enable ion-triggered disassembly and fluorescence control with valence-selectivity. Finally, the supramolecular aggregates are disassembled by alkaline phosphatase in a few minutes at room temperature, resulting in enzymatic control of fluorescence. These results highlight the interest of using a photoswitchable nucleotide binding partner as a self-assembly brick to build highly responsive supramolecular entities involving biological targets without the need to covalently modify them. Building stimuli-responsive supramolecular materials enables spatiotemporal control over complex systems, and is a promising strategy for a range of applications. Here, mixing adenosine 5’-triphosphate (ATP) with an azobenzene-guanidium compound possessing photodependent nucleotide binding affinity is shown to result in the spontaneous photo-reversible self-assembly of these compounds into micrometer-sized fluorescent aggregates that display dynamic responses to several chemical, physical and biological stimuli.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-22DOI: 10.1038/s42004-024-01223-1
Linfei Yang, Junwei Li, Dongzhou Zhang, Yuegao Liu, Qingyang Hu
In contrast to two-dimensional (2D) monolayer materials, van der Waals layered transition metal dichalcogenides exhibit rich polymorphism, making them promising candidates for novel superconductor, topological insulators and electrochemical catalysts. Here, we highlight the role of hydrostatic pressure on the evolution of electronic and crystal structures of layered ZrS2. Under deviatoric stress, our electrical experiments demonstrate a semiconductor-to-metal transition above 30.2 GPa, while quasi-hydrostatic compression postponed the metallization to 38.9 GPa. Both X-ray diffraction and Raman results reveal structural phase transitions different from those under hydrostatic pressure. Under deviatoric stress, ZrS2 rearranges the original ZrS6 octahedra into ZrS8 cuboids at 5.5 GPa, in which the unique cuboids coordination of Zr atoms is thermodynamically metastable. The structure collapses to a partially disordered phase at 17.4 GPa. These complex phase transitions present the importance of deviatoric stress on the highly tunable electronic properties of ZrS2 with possible implications for optoelectronic devices. Transition metal dichalcogenides exhibit rich polymorphism, making them promising candidates for superconductors, topological insulators, and electrochemical catalysts. Here, the authors study the metallization of non-hydrostatically compressed ZrS2 up to 45.8 GPa and find that a new high-pressure phase forms under deviatoric stress.
{"title":"Deviatoric stress-induced metallization, layer reconstruction and collapse of van der Waals bonded zirconium disulfide","authors":"Linfei Yang, Junwei Li, Dongzhou Zhang, Yuegao Liu, Qingyang Hu","doi":"10.1038/s42004-024-01223-1","DOIUrl":"10.1038/s42004-024-01223-1","url":null,"abstract":"In contrast to two-dimensional (2D) monolayer materials, van der Waals layered transition metal dichalcogenides exhibit rich polymorphism, making them promising candidates for novel superconductor, topological insulators and electrochemical catalysts. Here, we highlight the role of hydrostatic pressure on the evolution of electronic and crystal structures of layered ZrS2. Under deviatoric stress, our electrical experiments demonstrate a semiconductor-to-metal transition above 30.2 GPa, while quasi-hydrostatic compression postponed the metallization to 38.9 GPa. Both X-ray diffraction and Raman results reveal structural phase transitions different from those under hydrostatic pressure. Under deviatoric stress, ZrS2 rearranges the original ZrS6 octahedra into ZrS8 cuboids at 5.5 GPa, in which the unique cuboids coordination of Zr atoms is thermodynamically metastable. The structure collapses to a partially disordered phase at 17.4 GPa. These complex phase transitions present the importance of deviatoric stress on the highly tunable electronic properties of ZrS2 with possible implications for optoelectronic devices. Transition metal dichalcogenides exhibit rich polymorphism, making them promising candidates for superconductors, topological insulators, and electrochemical catalysts. Here, the authors study the metallization of non-hydrostatically compressed ZrS2 up to 45.8 GPa and find that a new high-pressure phase forms under deviatoric stress.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11193816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-20DOI: 10.1038/s42004-024-01218-y
Tom Burwell, Madasamy Thangamuthu, Gazi N. Aliev, Sadegh Ghaderzadeh, Emerson C. Kohlrausch, Yifan Chen, Wolfgang Theis, Luke T. Norman, Jesum Alves Fernandes, Elena Besley, Pete Licence, Andrei N. Khlobystov
A key strategy for minimizing our reliance on precious metals is to increase the fraction of surface atoms and improve the metal-support interface. In this work, we employ a solvent/ligand/counterion-free method to deposit copper in the atomic form directly onto a nanotextured surface of graphitized carbon nanofibers (GNFs). Our results demonstrate that under these conditions, copper atoms coalesce into nanoparticles securely anchored to the graphitic step edges, limiting their growth to 2–5 nm. The resultant hybrid Cu/GNF material displays high selectivity in the CO2 reduction reaction (CO2RR) for formate production with a faradaic efficiency of ~94% at -0.38 V vs RHE and a high turnover frequency of 2.78 × 106 h-1. The Cu nanoparticles adhered to the graphitic step edges significantly enhance electron transfer to CO2. Long-term CO2RR tests coupled with atomic-scale elucidation of changes in Cu/GNF reveal nanoparticles coarsening, and a simultaneous increase in the fraction of single Cu atoms. These changes in the catalyst structure make the onset of the CO2 reduction potential more negative, leading to less formate production at -0.38 V vs RHE, correlating with a less efficient competition of CO2 with H2O for adsorption on single Cu atoms on the graphitic surfaces, revealed by density functional theory calculations. A key strategy for minimizing our reliance on precious metal catalysts is to increase the fraction of surface atoms and improve the metal—support interface. Here, the authors develop a system in which nanoscale morphological changes in the catalyst are monitored and directly linked with the selectivity of the CO2 electroreduction reaction.
要最大限度地减少对贵金属的依赖，一个关键的策略就是增加表面原子的比例并改善金属-支撑界面。在这项工作中，我们采用了一种无溶剂/无配体/无计数器的方法，将原子形式的铜直接沉积在石墨化碳纳米纤维（GNFs）的纳米挤压表面上。我们的研究结果表明，在这些条件下，铜原子会凝聚成纳米颗粒，牢牢固定在石墨阶梯边缘，将其生长限制在 2-5 纳米。由此产生的 Cu/GNF 混合材料在二氧化碳还原反应（CO2RR）中显示出生产甲酸盐的高选择性，在 -0.38 V 相对于 RHE 时，远红外效率约为 94%，周转频率高达 2.78 × 106 h-1。附着在石墨阶梯边缘的铜纳米粒子显著增强了对 CO2 的电子转移。长期的 CO2RR 测试以及对 Cu/GNF 变化的原子尺度分析表明，纳米颗粒变粗，单个 Cu 原子的比例也同时增加。催化剂结构的这些变化使得二氧化碳还原电势的起始点更加消极，从而导致在 -0.38 V 与 RHE 值比较时甲酸盐生成量减少，这与密度泛函理论计算显示的二氧化碳与 H2O 在石墨表面单个铜原子上的吸附竞争效率降低有关。
{"title":"Direct formation of copper nanoparticles from atoms at graphitic step edges lowers overpotential and improves selectivity of electrocatalytic CO2 reduction","authors":"Tom Burwell, Madasamy Thangamuthu, Gazi N. Aliev, Sadegh Ghaderzadeh, Emerson C. Kohlrausch, Yifan Chen, Wolfgang Theis, Luke T. Norman, Jesum Alves Fernandes, Elena Besley, Pete Licence, Andrei N. Khlobystov","doi":"10.1038/s42004-024-01218-y","DOIUrl":"10.1038/s42004-024-01218-y","url":null,"abstract":"A key strategy for minimizing our reliance on precious metals is to increase the fraction of surface atoms and improve the metal-support interface. In this work, we employ a solvent/ligand/counterion-free method to deposit copper in the atomic form directly onto a nanotextured surface of graphitized carbon nanofibers (GNFs). Our results demonstrate that under these conditions, copper atoms coalesce into nanoparticles securely anchored to the graphitic step edges, limiting their growth to 2–5 nm. The resultant hybrid Cu/GNF material displays high selectivity in the CO2 reduction reaction (CO2RR) for formate production with a faradaic efficiency of ~94% at -0.38 V vs RHE and a high turnover frequency of 2.78 × 106 h-1. The Cu nanoparticles adhered to the graphitic step edges significantly enhance electron transfer to CO2. Long-term CO2RR tests coupled with atomic-scale elucidation of changes in Cu/GNF reveal nanoparticles coarsening, and a simultaneous increase in the fraction of single Cu atoms. These changes in the catalyst structure make the onset of the CO2 reduction potential more negative, leading to less formate production at -0.38 V vs RHE, correlating with a less efficient competition of CO2 with H2O for adsorption on single Cu atoms on the graphitic surfaces, revealed by density functional theory calculations. A key strategy for minimizing our reliance on precious metal catalysts is to increase the fraction of surface atoms and improve the metal—support interface. Here, the authors develop a system in which nanoscale morphological changes in the catalyst are monitored and directly linked with the selectivity of the CO2 electroreduction reaction.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01218-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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