Ranran Zhang, Dan Li, Zhifang Zhou, Haofei Hong, Jie Shi, Zhimeng Wu
Bovine milk exosomes (BmExo) have been identified as versatile nanovesicles for anti-cancer drugs delivery due to their natural availability and biocompatibility. However, tumor-specific delivery based on BmExo often requires post-isolation modifications of the membrane surface with active-targeting ligands. In this study, we report an alternative approach to functionalize BmExo with nanobody using Sortase A-mediated site-specific ligation for drug delivery. The BmExo membrane was first coated with a diglycine-containing amphiphile molecule, NH2-GG-PEG2000-DSPE, through hydrophobic insertion, following by ligation with EGFR nanobody (7D12) by Sortase A (SrtA). The successful construction of BmExo-7D12 was confirmed by Western blotting analysis, electron microscopy, and dynamic light scattering (DLS). As a demonstration model, BmExo-7D12 loaded with the chemotherapeutic drug doxorubicin (Dox) was shown to be able to deliver Dox to cancer cells in response to the expression of EGFR as manifested by immunocytochemistry and flow cytometry analysis. Finally, the cytotoxicity assay showed that BmExo-7D12-Dox was more effective in killing tumor cells with high EGFR expression while significantly reduced the non-specific toxicity to EGFR negative cells. This study developed an effective approach to functionalize BmExo with nanobody for target-specific drug delivery. This approach should prove to be versatile and efficient for the generation of protein-ligands modified BmExo.
{"title":"Chemo-enzymatic Functionalization of Bovine Milk Exosomes with an EGFR Nanobody for Target-specific Drug Delivery.","authors":"Ranran Zhang, Dan Li, Zhifang Zhou, Haofei Hong, Jie Shi, Zhimeng Wu","doi":"10.1002/cbic.202400512","DOIUrl":"https://doi.org/10.1002/cbic.202400512","url":null,"abstract":"<p><p>Bovine milk exosomes (BmExo) have been identified as versatile nanovesicles for anti-cancer drugs delivery due to their natural availability and biocompatibility. However, tumor-specific delivery based on BmExo often requires post-isolation modifications of the membrane surface with active-targeting ligands. In this study, we report an alternative approach to functionalize BmExo with nanobody using Sortase A-mediated site-specific ligation for drug delivery. The BmExo membrane was first coated with a diglycine-containing amphiphile molecule, NH2-GG-PEG2000-DSPE, through hydrophobic insertion, following by ligation with EGFR nanobody (7D12) by Sortase A (SrtA). The successful construction of BmExo-7D12 was confirmed by Western blotting analysis, electron microscopy, and dynamic light scattering (DLS). As a demonstration model, BmExo-7D12 loaded with the chemotherapeutic drug doxorubicin (Dox) was shown to be able to deliver Dox to cancer cells in response to the expression of EGFR as manifested by immunocytochemistry and flow cytometry analysis. Finally, the cytotoxicity assay showed that BmExo-7D12-Dox was more effective in killing tumor cells with high EGFR expression while significantly reduced the non-specific toxicity to EGFR negative cells. This study developed an effective approach to functionalize BmExo with nanobody for target-specific drug delivery. This approach should prove to be versatile and efficient for the generation of protein-ligands modified BmExo.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dina Iebed, Tobias Gökler, Hugo van Ingen, Anne Claire Conibear
Intrinsically disordered proteins are abundant in the nucleus and are prime sites for posttranslational modifications that modulate transcriptional regulation. Lacking a defined three-dimensional structure, intrinsically disordered proteins populate an ensemble of several conformational states, which are dynamic and often altered by posttranslational modifications, or by binding to interaction partners. Although there is growing appreciation for the role that intrinsically disordered regions have in regulating protein-protein interactions, we still have a poor understanding of how to determine conformational population shifts, their causes under various conditions, and how to represent and model conformational ensembles. Here, we study the effects of serine phosphorylation in the nucleosome-binding domain of an intrinsically disordered protein - HMGN1 - using NMR spectroscopy, circular dichroism and modelling of protein complexes. We show that phosphorylation induces local conformational changes in the peptide backbone and decreases the helical propensity of the nucleosome binding domain. Modelling studies using AlphaFold3 suggest that phosphorylation disrupts the interface between HMGN1 and the nucleosome acidic patch, but that the models over-predict helicity in comparison to experimental data. These studies help us to build a picture of how posttranslational modifications might shift the conformational populations of disordered regions, alter access to histones, and regulate chromatin compaction.
{"title":"Phosphorylation of the HMGN1 nucleosome binding domain decreases helicity and interactions with the acidic patch.","authors":"Dina Iebed, Tobias Gökler, Hugo van Ingen, Anne Claire Conibear","doi":"10.1002/cbic.202400589","DOIUrl":"https://doi.org/10.1002/cbic.202400589","url":null,"abstract":"<p><p>Intrinsically disordered proteins are abundant in the nucleus and are prime sites for posttranslational modifications that modulate transcriptional regulation. Lacking a defined three-dimensional structure, intrinsically disordered proteins populate an ensemble of several conformational states, which are dynamic and often altered by posttranslational modifications, or by binding to interaction partners. Although there is growing appreciation for the role that intrinsically disordered regions have in regulating protein-protein interactions, we still have a poor understanding of how to determine conformational population shifts, their causes under various conditions, and how to represent and model conformational ensembles. Here, we study the effects of serine phosphorylation in the nucleosome-binding domain of an intrinsically disordered protein - HMGN1 - using NMR spectroscopy, circular dichroism and modelling of protein complexes. We show that phosphorylation induces local conformational changes in the peptide backbone and decreases the helical propensity of the nucleosome binding domain. Modelling studies using AlphaFold3 suggest that phosphorylation disrupts the interface between HMGN1 and the nucleosome acidic patch, but that the models over-predict helicity in comparison to experimental data. These studies help us to build a picture of how posttranslational modifications might shift the conformational populations of disordered regions, alter access to histones, and regulate chromatin compaction.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pierre J Obeid, Paolo Yammine, Hanna El-Nakat, Rima Kassab, Tony Tannous, Zeina Nasr, Therese Maarawi, Norma Dahdah, Ali El Safadi, Agapy Mansour, Ayman Chmayssem
Organ-On-a-Chip (OOC) is a multichannel 3D-microfluidic cell-culture system included in a chip that stimulates the behavior of an organ. This technology relies on a multidisciplinary science benefiting from and helping in the progress of many fields including microbiology, microfluidics, biomaterials, and bioengineering. This review article summarizes the progress and achievements of various organ-on-chip technologies. It highlights the significant advantages of this technology in terms of reducing animal testing and providing personalized medical responses. In addition, this paper demonstrates how OOC is becoming a promising and powerful tool in pharmaceutical research to combat diseases. It predicts not only the effects of drugs on the target organs but also, using body-on-a-chip systems, it may provide insights into the side effects of the drug delivery on the other organs. Likewise, the models used for the construction of various organ-on-a-chip are investigated along with the design and materials of microfluidic devices. For each OOC, the integrated monitoring devices within the chips (e.g., sensors and biosensors) are discussed. We also discussed the evolution of FDA regulations and the potential in the near future for integrating OOCs in protocols approval that support and reduce the need and the failure rates in preclinical and clinical studies.
{"title":"Organ-On-a-Chip devices: Technology Progress and Challenges.","authors":"Pierre J Obeid, Paolo Yammine, Hanna El-Nakat, Rima Kassab, Tony Tannous, Zeina Nasr, Therese Maarawi, Norma Dahdah, Ali El Safadi, Agapy Mansour, Ayman Chmayssem","doi":"10.1002/cbic.202400580","DOIUrl":"https://doi.org/10.1002/cbic.202400580","url":null,"abstract":"<p><p>Organ-On-a-Chip (OOC) is a multichannel 3D-microfluidic cell-culture system included in a chip that stimulates the behavior of an organ. This technology relies on a multidisciplinary science benefiting from and helping in the progress of many fields including microbiology, microfluidics, biomaterials, and bioengineering. This review article summarizes the progress and achievements of various organ-on-chip technologies. It highlights the significant advantages of this technology in terms of reducing animal testing and providing personalized medical responses. In addition, this paper demonstrates how OOC is becoming a promising and powerful tool in pharmaceutical research to combat diseases. It predicts not only the effects of drugs on the target organs but also, using body-on-a-chip systems, it may provide insights into the side effects of the drug delivery on the other organs. Likewise, the models used for the construction of various organ-on-a-chip are investigated along with the design and materials of microfluidic devices. For each OOC, the integrated monitoring devices within the chips (e.g., sensors and biosensors) are discussed. We also discussed the evolution of FDA regulations and the potential in the near future for integrating OOCs in protocols approval that support and reduce the need and the failure rates in preclinical and clinical studies.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wei-Siang Kao, Wei Huang, Yunlei Zhang, Kangqiao Wen, Andrea Meyer, Jorge Escorihuela, Scott Laughlin
Bioorthogonal chemistry has become a mainstay in chemical biology and is making inroads in the clinic with recent advances in protein targeting and drug release. Since the field's beginning, a major focus has been on designing bioorthogonal reagents with good selectivity, reactivity, and stability in complex biological environments. More recently, chemists have imbued reagents with new functionalities like click-and-release or light/enzyme-controllable reactivity. We have previously developed a controllable cyclopropene-based bioorthogonal ligation, which has excellent stability in physiological conditions and can be triggered to react with tetrazines by exposure to enzymes, biologically significant small molecules, or light spanning the visual spectrum. Here, to improve reactivity and gain a better understanding of this system, we screened diene reaction partners for the cyclopropene. We found that a cyclopropene-quinone pair is 26 times faster than reactions with 1,2,4,5-tetrazines. Additionally, we showed that the reaction of the cyclopropene-quinone pair can be activated by two orthogonal mechanisms, caging group removal on the cyclopropene and oxidation/reduction of the quinone. Finally, we demonstrated that this caged cyclopropene-quinone can be used as a bioorthogonal imaging tool to label the membranes of fixed, cultured cells.
{"title":"Redox-Activated Substrates for Enhancing Activatable Cyclopropene Bioorthogonal Reactions.","authors":"Wei-Siang Kao, Wei Huang, Yunlei Zhang, Kangqiao Wen, Andrea Meyer, Jorge Escorihuela, Scott Laughlin","doi":"10.1002/cbic.202400304","DOIUrl":"https://doi.org/10.1002/cbic.202400304","url":null,"abstract":"<p><p>Bioorthogonal chemistry has become a mainstay in chemical biology and is making inroads in the clinic with recent advances in protein targeting and drug release. Since the field's beginning, a major focus has been on designing bioorthogonal reagents with good selectivity, reactivity, and stability in complex biological environments. More recently, chemists have imbued reagents with new functionalities like click-and-release or light/enzyme-controllable reactivity. We have previously developed a controllable cyclopropene-based bioorthogonal ligation, which has excellent stability in physiological conditions and can be triggered to react with tetrazines by exposure to enzymes, biologically significant small molecules, or light spanning the visual spectrum. Here, to improve reactivity and gain a better understanding of this system, we screened diene reaction partners for the cyclopropene. We found that a cyclopropene-quinone pair is 26 times faster than reactions with 1,2,4,5-tetrazines. Additionally, we showed that the reaction of the cyclopropene-quinone pair can be activated by two orthogonal mechanisms, caging group removal on the cyclopropene and oxidation/reduction of the quinone. Finally, we demonstrated that this caged cyclopropene-quinone can be used as a bioorthogonal imaging tool to label the membranes of fixed, cultured cells.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Protein phosphatase-1 (PP1) is a ubiquitous enzyme counteracting hundreds of kinases in cells. PP1 interacts with regulatory proteins via an RVxF peptide motif that binds to a hydrophobic groove on the enzyme. PP1-disrupting peptides (PDPs) compete with these regulatory proteins, leading to the release of the active PP1 subunit and promoting substrate dephosphorylation. Building on previous strategies employing the ortho-nitrobenzyl (o-Nb) group, we introduced coumarin derivatives into a PDP via an ether bond to explore their effects on PP1 activity. Surprisingly, our study revealed that the coumarin-caged peptides (PDP-DEACM and PDP-CM) underwent a photo-Claisen rearrangement, resulting in an unexpected hyperactivation of PP1. Our findings underscore the importance of linker design in controlling uncaging efficiency and highlight the need for comprehensive in vitro analysis before cellular experiments.
{"title":"Photo-Claisen Rearrangement in a Coumarin-Caged Peptide leads to a Surprising Enzyme Hyperactivation.","authors":"Corina Maller, Eirini Marouda, Maja Köhn","doi":"10.1002/cbic.202400561","DOIUrl":"https://doi.org/10.1002/cbic.202400561","url":null,"abstract":"<p><p>Protein phosphatase-1 (PP1) is a ubiquitous enzyme counteracting hundreds of kinases in cells. PP1 interacts with regulatory proteins via an RVxF peptide motif that binds to a hydrophobic groove on the enzyme. PP1-disrupting peptides (PDPs) compete with these regulatory proteins, leading to the release of the active PP1 subunit and promoting substrate dephosphorylation. Building on previous strategies employing the ortho-nitrobenzyl (o-Nb) group, we introduced coumarin derivatives into a PDP via an ether bond to explore their effects on PP1 activity. Surprisingly, our study revealed that the coumarin-caged peptides (PDP-DEACM and PDP-CM) underwent a photo-Claisen rearrangement, resulting in an unexpected hyperactivation of PP1. Our findings underscore the importance of linker design in controlling uncaging efficiency and highlight the need for comprehensive in vitro analysis before cellular experiments.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kien Voon Kong, Melody Cai-Syaun Wu, Jack Hau-Ting Wei, Ricky Yu-Syun Fan, Eng Zhi Sim, Ken-Tye Yong, Tianxun Gong
BODIPY analogs are promising photosensitizers for molecular phototherapy; however, they exhibit high dark cytotoxicity and limited singlet oxygen generation capacity. In this study, we developed self-assembled core-shell nanophotosensitizers by linking a bipyridine group to BODIPY (Bpy-BODIPY) and promoting J-aggregation on gold nanourchins. This design enhances photostability and reduces the energy gap between the lowest singlet excited state and the lower triplet state, facilitating efficient singlet oxygen production. Notably, Bpy-BODIPY@Au significantly suppresses tau protein aggregation and enhances neuroprotective action, even in the presence of a phosphatase inhibitor. This work broadens the application of BODIPY chemistry to nanoagents for neuroprotective therapy.
{"title":"Self-Assembled BODIPY@Au Core-Shell Structures for Durable Neuroprotective Phototherapy.","authors":"Kien Voon Kong, Melody Cai-Syaun Wu, Jack Hau-Ting Wei, Ricky Yu-Syun Fan, Eng Zhi Sim, Ken-Tye Yong, Tianxun Gong","doi":"10.1002/cbic.202400562","DOIUrl":"https://doi.org/10.1002/cbic.202400562","url":null,"abstract":"<p><p>BODIPY analogs are promising photosensitizers for molecular phototherapy; however, they exhibit high dark cytotoxicity and limited singlet oxygen generation capacity. In this study, we developed self-assembled core-shell nanophotosensitizers by linking a bipyridine group to BODIPY (Bpy-BODIPY) and promoting J-aggregation on gold nanourchins. This design enhances photostability and reduces the energy gap between the lowest singlet excited state and the lower triplet state, facilitating efficient singlet oxygen production. Notably, Bpy-BODIPY@Au significantly suppresses tau protein aggregation and enhances neuroprotective action, even in the presence of a phosphatase inhibitor. This work broadens the application of BODIPY chemistry to nanoagents for neuroprotective therapy.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Knud J Jensen, Haoyu Chen, Narendra Kumar Mishra, Manuel C Martos-Maldonado, Sandie B Roholm, Kasper Kildegaard Sørensen
Chemical modification of proteins is of growing importance to generate new molecular probes for chemical biology and for the development of new biopharmaceuticals. For example, two approved, long-acting insulin variants are lipidated at the LysB29 side-chain. Acylations of proteins have so far been performed in batch-mode. Here we describe the use of flow chemistry for site-selective acylation of a small protein, insulin. To the best of our knowledge this is the first report on flow chemistry for chemical modification of insulin. The first step was to develop reaction conditions for acylation of Lys B29 that gave a soluble mixture and thus was compatible with flow chemistry in a microreactor; this included selection of a soluble base. Secondly, the conditions, such as reagent ratios and flow rate were optimized. Third, the use of these conditions for the acylation with a wide range of acids was demonstrated. Finally, Boc-protected insulins were synthesized. Insulin remained stable towards these flow chemistry conditions. This use of flow chemistry for the chemical modification of insulin opens the prospect of producing chemically modified biopharmaceuticals by flow chemistry with fewer byproducts.
{"title":"Chemical Modification of Insulin Using Flow Chemistry.","authors":"Knud J Jensen, Haoyu Chen, Narendra Kumar Mishra, Manuel C Martos-Maldonado, Sandie B Roholm, Kasper Kildegaard Sørensen","doi":"10.1002/cbic.202400534","DOIUrl":"https://doi.org/10.1002/cbic.202400534","url":null,"abstract":"<p><p>Chemical modification of proteins is of growing importance to generate new molecular probes for chemical biology and for the development of new biopharmaceuticals. For example, two approved, long-acting insulin variants are lipidated at the LysB29 side-chain. Acylations of proteins have so far been performed in batch-mode. Here we describe the use of flow chemistry for site-selective acylation of a small protein, insulin. To the best of our knowledge this is the first report on flow chemistry for chemical modification of insulin. The first step was to develop reaction conditions for acylation of Lys B29 that gave a soluble mixture and thus was compatible with flow chemistry in a microreactor; this included selection of a soluble base. Secondly, the conditions, such as reagent ratios and flow rate were optimized. Third, the use of these conditions for the acylation with a wide range of acids was demonstrated. Finally, Boc-protected insulins were synthesized. Insulin remained stable towards these flow chemistry conditions. This use of flow chemistry for the chemical modification of insulin opens the prospect of producing chemically modified biopharmaceuticals by flow chemistry with fewer byproducts.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mapping the endocytic vesicular acidification process is of prior importance to better understand the health and pathological processes of cells. Herein, by integrating a pH-sensitive i-motif and a pair of fluorescence resonance energy transfer (FRET) into a tetrahedral DNA framework (TDF), we develop a pH-responsive DNA nanomachine, allowing for efficient sensing of pH from 7.0 to 5.5 via the pH-triggered spatial proximity modulation of FRET. The inheriting endo-lysosome-targeting ability of TDF enables spatiotemporal tracking of endocytic vesicle acidification during the endosomal maturation process. Analysis of pH-dependent FRET response at single fluorescent spot level reveals the significant difference of endocytic vesicular acidification between normal and cancer cells. The performance of pH-responsive DNA nanomachine underlines its potential for studies on vesicle acidification-related pathologies as a universal platform.
绘制内囊酸化过程图对于更好地了解细胞的健康和病理过程具有重要意义。在这里,我们将 pH 敏感的 i-motif 和一对荧光共振能量转移(FRET)整合到一个四面体 DNA 框架(TDF)中,开发出一种 pH 响应型 DNA 纳米机械,通过 pH 触发的 FRET 空间接近调制,有效感知 7.0 到 5.5 的 pH 值。TDF继承了内溶酶体的靶向能力,可以在内含体成熟过程中对内含囊酸化进行时空跟踪。在单个荧光点水平上分析 pH 依赖性 FRET 响应,可以发现正常细胞和癌细胞的内囊酸化存在显著差异。pH 响应 DNA 纳米机器的性能突出了它作为一个通用平台在研究囊泡酸化相关病理学方面的潜力。
{"title":"Mapping Endocytic Vesicular Acidification with a pH-Responsive DNA Nanomachine.","authors":"Xiaodong Xie, Zhiyuan Liu, Xuelin Xiang, Shaopeng Wang, Zhaoshuai Gao, Lifeng Xu, Fei Ding, Qian Li","doi":"10.1002/cbic.202400363","DOIUrl":"https://doi.org/10.1002/cbic.202400363","url":null,"abstract":"<p><p>Mapping the endocytic vesicular acidification process is of prior importance to better understand the health and pathological processes of cells. Herein, by integrating a pH-sensitive i-motif and a pair of fluorescence resonance energy transfer (FRET) into a tetrahedral DNA framework (TDF), we develop a pH-responsive DNA nanomachine, allowing for efficient sensing of pH from 7.0 to 5.5 via the pH-triggered spatial proximity modulation of FRET. The inheriting endo-lysosome-targeting ability of TDF enables spatiotemporal tracking of endocytic vesicle acidification during the endosomal maturation process. Analysis of pH-dependent FRET response at single fluorescent spot level reveals the significant difference of endocytic vesicular acidification between normal and cancer cells. The performance of pH-responsive DNA nanomachine underlines its potential for studies on vesicle acidification-related pathologies as a universal platform.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yanli Lei, Lihong Yu, Zeyang Yang, Ke Quan, Zhihe Qing
Platinum (Pt) nanozymes with multiple intrinsic enzyme-mimicking activities have attracted extensive attention in biomedical fields due to their high catalytic activity, ease of modification, and convenient storage. However, the Pt nanozymes synthesized by the traditional method often suffer from uncontrollable morphology and poor stability under physicochemical conditions, resulting in unsatisfactory catalytic behavior in practical applications. To optimize the catalytic ability, biological templates have been introduced recently, which can guide the deposition of platinum ions on their surface to form specific morphologies and then stabilize the resulting Pt nanozymes. Given the promising potential of biotemplated Pt nanozymes in practical applications, it is essential to conduct a systematic and comprehensive review to summarize their recent research progress. In this review, we first categorize the biological templates and discussed the mechanisms as well as characteristics of each type of biotemplate in directing the growth of Pt nanozyme. Factors that impact the growth of biotemplated Pt nanozymes are then analyzed, followed by summarizing their biomedical application. Finally, the challenges and opportunities in this field are outlined. This review article aims to provide theoretical guidance for developing Pt nanozymes with robust functionalities in biomedical applications.
{"title":"Biotemplated Platinum Nanozymes: Synthesis, Catalytic Regulation and Biomedical Applications.","authors":"Yanli Lei, Lihong Yu, Zeyang Yang, Ke Quan, Zhihe Qing","doi":"10.1002/cbic.202400548","DOIUrl":"https://doi.org/10.1002/cbic.202400548","url":null,"abstract":"<p><p>Platinum (Pt) nanozymes with multiple intrinsic enzyme-mimicking activities have attracted extensive attention in biomedical fields due to their high catalytic activity, ease of modification, and convenient storage. However, the Pt nanozymes synthesized by the traditional method often suffer from uncontrollable morphology and poor stability under physicochemical conditions, resulting in unsatisfactory catalytic behavior in practical applications. To optimize the catalytic ability, biological templates have been introduced recently, which can guide the deposition of platinum ions on their surface to form specific morphologies and then stabilize the resulting Pt nanozymes. Given the promising potential of biotemplated Pt nanozymes in practical applications, it is essential to conduct a systematic and comprehensive review to summarize their recent research progress. In this review, we first categorize the biological templates and discussed the mechanisms as well as characteristics of each type of biotemplate in directing the growth of Pt nanozyme. Factors that impact the growth of biotemplated Pt nanozymes are then analyzed, followed by summarizing their biomedical application. Finally, the challenges and opportunities in this field are outlined. This review article aims to provide theoretical guidance for developing Pt nanozymes with robust functionalities in biomedical applications.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peibin Yue, Yue Chen, Monday O Ogese, Shan Sun, Xiaolei Zhang, Taiwo Esan, John K Buolamwini, James Turkson
Aberrantly-active signal transducer and activator of transcription (Stat)3 has a causal role in many human cancers and represents a validated anticancer drug target, though it has posed significant challenge to drug development. A new small molecule, JKB887, was identified through virtual library screening and is predicted to interact with Lys591, Arg609 and Pro63 in the phospho-tyrosine (pTyr)-binding pocket of the Stat3 SH2 domain. JKB887 inhibited Stat3 DNA-binding activity in vitro in a time-dependent manner, with IC50 of 2.2-4.5 µM at 30-60-min incubation. It directly disrupted both the Stat3 binding to the cognate, high-affinity pTyr (pY) peptide, GpYLPQTV-NH2 in fluorescent polarization assay with IC50 of 3.5-5.5 µM at 60-90-min incubation, and to the IL-6 receptor/gp130 or Src in treated malignant cells. Treatment with JKB887 selectively blocked constitutive Stat3 phosphorylation, nuclear translocation and transcriptional activity, Stat3-regulated gene expression, and decreased viable cell numbers, cell growth, colony formation, migration, and survival in human or mouse tumor cells. By contrast, JKB887 had minimal effects on Stat1 activity, pErk1/2MAPK, pShc, pJAK2, pSrc induction, or cells that do not harbor aberrantly-active Stat3. Additionally, JKB887 inhibited growth of human breast cancer xenografts in mice. JKB887 is a Stat3-selective inhibitor with demonstrable antitumor effects against Stat3-dependent human cancers.
{"title":"SMALL MOLECULE INDUCES TIME-DEPENDENT INHIBITION OF STAT3 DIMERIZATION AND DNA-BINDING ACTIVITY AND REGRESSES HUMAN BREAST TUMOR XENOGRAFTS.","authors":"Peibin Yue, Yue Chen, Monday O Ogese, Shan Sun, Xiaolei Zhang, Taiwo Esan, John K Buolamwini, James Turkson","doi":"10.1002/cbic.202400351","DOIUrl":"https://doi.org/10.1002/cbic.202400351","url":null,"abstract":"<p><p>Aberrantly-active signal transducer and activator of transcription (Stat)3 has a causal role in many human cancers and represents a validated anticancer drug target, though it has posed significant challenge to drug development. A new small molecule, JKB887, was identified through virtual library screening and is predicted to interact with Lys591, Arg609 and Pro63 in the phospho-tyrosine (pTyr)-binding pocket of the Stat3 SH2 domain. JKB887 inhibited Stat3 DNA-binding activity in vitro in a time-dependent manner, with IC50 of 2.2-4.5 µM at 30-60-min incubation. It directly disrupted both the Stat3 binding to the cognate, high-affinity pTyr (pY) peptide, GpYLPQTV-NH2 in fluorescent polarization assay with IC50 of 3.5-5.5 µM at 60-90-min incubation, and to the IL-6 receptor/gp130 or Src in treated malignant cells. Treatment with JKB887 selectively blocked constitutive Stat3 phosphorylation, nuclear translocation and transcriptional activity, Stat3-regulated gene expression, and decreased viable cell numbers, cell growth, colony formation, migration, and survival in human or mouse tumor cells. By contrast, JKB887 had minimal effects on Stat1 activity, pErk1/2MAPK, pShc, pJAK2, pSrc induction, or cells that do not harbor aberrantly-active Stat3. Additionally, JKB887 inhibited growth of human breast cancer xenografts in mice. JKB887 is a Stat3-selective inhibitor with demonstrable antitumor effects against Stat3-dependent human cancers.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}