Chemical Science最新文献_第5页

Engineering antisense oligonucleotides for targeted mRNA degradation through lysosomal trafficking 工程反义寡核苷酸通过溶酶体运输靶向mRNA降解

IF 8.4 1区化学

Chemical Science Pub Date : 2025-06-09 DOI: 10.1039/d5sc03751d

Disha Kashyap, Thomas Milne, Michael John Booth

{"title":"Engineering antisense oligonucleotides for targeted mRNA degradation through lysosomal trafficking","authors":"Disha Kashyap, Thomas Milne, Michael John Booth","doi":"10.1039/d5sc03751d","DOIUrl":"https://doi.org/10.1039/d5sc03751d","url":null,"abstract":"Antisense oligonucleotides (ASOs) can modulate gene expression at the mRNA level, providing the ability to tackle conventionally undruggable targets and usher in an era of personalized medicine. A key mode of action for ASOs relies upon RNase H-engagement in the nucleus, however, most mature mRNA is present in the cytoplasm. This disconnect limits the efficacy and biomedical applications of ASOs. In this paper, we have established a new mechanism of action for achieving potent and targeted mRNA knockdown by leveraging a lysosomal degradation pathway. To achieve this, we employ autophagosome-tethering compound (ATTEC) technology that utilises bifunctional small molecules for lysosomal trafficking. In this manner, to induce degradation of target mRNA located in the cytoplasm, we conjugated an ATTEC warhead, ispinesib, to RNase H-inactive ASOs. These fully 2′-O-Methylated RNase H-inactive ASOs have higher chemical stability and tighter mRNA binding than conventional ‘gapmer’ sequences, but cannot be recognised by RNase H. Using our lysosomal trafficking antisense oligonucleotide (LyTON) technology, we show significant lysosome-dependent knockdown of multiple molecular targets in various cell lines, via transfection and gymnotic uptake. The LyTON modification is also able to boost the knockdown efficacy of RNase H-active 'gapmer' ASOs. Engineered to degrade mRNA independent of RNase H recognition, LyTONs will enable gene silencing using oligonucleotide chemistries with higher chemical stability, tighter mRNA binding affinity, and improved cell delivery profiles. This will enable us to target a wider range of disease-relevant mRNA, potentially leading to the development of new therapies.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"26 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Stretchable Electrode Enabled Electrochemical Mass Spectrometry for In Situ and Complementary Analysis of Cellular Mechanotransduction 可拉伸电极电化学质谱法用于细胞机械传导的原位和互补分析

IF 8.4 1区化学

Chemical Science Pub Date : 2025-06-09 DOI: 10.1039/d5sc02191j

Haotian Wang, Jing Yan, Jiamei Lin, Caiying Zhang, Xinglei Zhang, Rui Su, Yan-Ling Liu, Jiaquan Xu

{"title":"Stretchable Electrode Enabled Electrochemical Mass Spectrometry for In Situ and Complementary Analysis of Cellular Mechanotransduction","authors":"Haotian Wang, Jing Yan, Jiamei Lin, Caiying Zhang, Xinglei Zhang, Rui Su, Yan-Ling Liu, Jiaquan Xu","doi":"10.1039/d5sc02191j","DOIUrl":"https://doi.org/10.1039/d5sc02191j","url":null,"abstract":"Mechanotransduction exerts a profound influence on diverse cellular processes via the activated signalling pathways. Although the currently established methods could reveal force-induced ultimate changes in specific biochemical cues, they fail to provide the real-time and comprehensive information about the complicated signaling events. Herein, we report a stretchable electrode enabled electrochemical mass spectrometry for in situ and complementary analysis of cellular mechanotransduction. The stretchable electrode functions as not only an electrochemical sensor for tracking the electroactive molecules released from stretched-cells cultured thereon, but also an ionization source to ionize the intracellular metabolites for mass spectrometry analysis. As a concept application, the endothelial mechanotransduction mediated NO pathway was found to be different in transient stimulation and prolonged stimulation for the first time. This work provides a revealing strategy for in situ and comprehensive analysis of the biomolecules involved in cellular mechanotransduction.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"6 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144238197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Mechanism of Spin-Phonon Relaxation in Endohedral Metallofullerene Single Molecule Magnets 内嵌金属富勒烯单分子磁体的自旋声子弛豫机制

IF 8.4 1区化学

Chemical Science Pub Date : 2025-06-09 DOI: 10.1039/d4sc07786e

Tanu Sharma, Rupesh Kumar Tiwari, Sourav Dey, Antonio Mariano, Alessandro Lunghi, Gopalan Rajaraman

{"title":"The Mechanism of Spin-Phonon Relaxation in Endohedral Metallofullerene Single Molecule Magnets","authors":"Tanu Sharma, Rupesh Kumar Tiwari, Sourav Dey, Antonio Mariano, Alessandro Lunghi, Gopalan Rajaraman","doi":"10.1039/d4sc07786e","DOIUrl":"https://doi.org/10.1039/d4sc07786e","url":null,"abstract":"This study presents the first-ever investigation of spin-phonon coupling mechanisms in fullerene-based single-molecule magnets (SMMs) using ab initio CASSCF combined with DFT calculations. While lanthanide-based SMMs, particularly those with DyIII ions, are known for their impressive blocking temperatures and relaxation barriers, endohedral metallofullerene (EMFs) offer a unique platform for housing low-coordinated lanthanides within rigid carbon cages. We have explored the spin dynamics of in DyScS@C82 exhibiting among the highest blocking temperature (TB) reported. Through our computational analysis, we reveal that while the fullerene cage enhances crystal field splitting and provides structural stability without significantly contributing to spin-relaxation-driving low-energy phonons, the internal ionic motion emerges as the primary factor controlling spin relaxation and limiting blocking temperature. This computational investigation into the spin dynamics of EMF-based SMMs provides key insights into their magnetic behaviour for the first time and suggests potential strategies for improving their performance towards futuristic SMMs.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"16 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144238198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Ultrahigh photocatalytic hydrogen evolution of linear conjugated terpolymers enabled by an ultra-low ratio of the benzothiadiazole monomer 校正：超低比例的苯并噻唑单体使线性共轭三元聚合物的超高光催化析氢成为可能

IF 8.4 1区化学

Chemical Science Pub Date : 2025-06-09 DOI: 10.1039/d5sc90121a

Zheng-Hui Xie, Gang Ye, Hao Gong, Pachaiyappan Murugan, Can Lang, Yi-Fan Dai, Kai Yang, Shi-Yong Liu

引用次数: 0

“Dual lock-and-key” Triggered and Endoplasmic Reticulum Targeting Nanophotosensitizers for Activatable Type-I Photodynamic and Photothermal Therapies “双锁-钥匙”触发和内质网靶向纳米光敏剂用于可激活的i型光动力和光热治疗

IF 8.4 1区化学

Chemical Science Pub Date : 2025-06-09 DOI: 10.1039/d5sc01987g

Rumeng Zhan, Weijie Zhou, Hongyu Ma, Menghui Zou, Mingming Zhang, Weian Zhang, Jia Tian

{"title":"“Dual lock-and-key” Triggered and Endoplasmic Reticulum Targeting Nanophotosensitizers for Activatable Type-I Photodynamic and Photothermal Therapies","authors":"Rumeng Zhan, Weijie Zhou, Hongyu Ma, Menghui Zou, Mingming Zhang, Weian Zhang, Jia Tian","doi":"10.1039/d5sc01987g","DOIUrl":"https://doi.org/10.1039/d5sc01987g","url":null,"abstract":"Photodynamic therapy (PDT) has emerged as a critical modality in cancer treatment with the merits of non-invasiveness, spatiotemporal control, and minimal drug resistance. However, the clinical application of PDT is often hindered by the inherent limitations of side effects caused by “always on” state of reactive oxygen species (ROS) and low ROS generation efficiency in hypoxic tumors. To overcome these limitations, we developed a tumor microenvironment (TME) “dual lock-and-key” triggered and Endoplasmic Reticulum (ER) Targeting nanophotosensitizerr for fluorescence imaging-guided activatable Type-I PDT and photothermal therapy (PTT). This “smart” nanophotosensitizer maintains an \"off\" state during systemic circulation, and specifically activated only in acidic and GSH-overexpressed TME (\"on\" state), where the fluorescence, ROS generation, and photothermal photothermal conversion capabilities were recovered, leading to precise and enhanced phototherapies in tumor sites with minimizing side effects. Sulfur-substituted and ER-targeting hemicyanine leads to a large red-shift absorption, concurrent Type-I ROS production and photothermal conversion on ER, thereby enhanced protein deactivation and ER stress. Comprehensive in vitro and in vivo investigations demonstrated that the TME dual triggered activatable nanophotosesitizer, upon NIR laser irradiation, effectively kill tumor cells, and significantly suppressing tumor growth by fluorescence imaging-guided Type-I PDT and PTT. This work provides a pathway for developing tumor microenvironment-triggered precise phototherapeutics with improved biosafety and clinical translation potential.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"47 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144238175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Diastereoselective Scholl reaction: Point-to-helical chirality transfer in molecular nanographenes 非对映选择性Scholl反应：分子纳米石墨烯中的点-螺旋手性转移

IF 8.4 1区化学

Chemical Science Pub Date : 2025-06-09 DOI: 10.1039/d5sc02563j

Sergio Marcos López, Manuel Buendía, Israel Fernández, Salvatore Filippone, Nazario Martín

引用次数: 0

Engineering charge transfer by tethering halogens onto covalent organic framework for photocatalytic sacrificial hydrogen evolution 通过将卤素系在共价有机框架上进行光催化牺牲析氢的工程电荷转移

IF 8.4 1区化学

Chemical Science Pub Date : 2025-06-06 DOI: 10.1039/d5sc00082c

Fang Pei Ma, Xiao Chi, Ying Wen, Qihong Yue, Tao Chen, Xiaojiang Yu, Xiaoling Liu, Yu Zhou, Jun Wang

{"title":"Engineering charge transfer by tethering halogens onto covalent organic framework for photocatalytic sacrificial hydrogen evolution","authors":"Fang Pei Ma, Xiao Chi, Ying Wen, Qihong Yue, Tao Chen, Xiaojiang Yu, Xiaoling Liu, Yu Zhou, Jun Wang","doi":"10.1039/d5sc00082c","DOIUrl":"https://doi.org/10.1039/d5sc00082c","url":null,"abstract":"Covalent organic frameworks (COFs) are promising versatile organic semiconductors for the photocatalytic hydrogen evolution reaction (HER), but usually rely on the utilization of expensive Pt species as the co-catalyst and exhibit inferior activity in seawater relative to pure water. Herein, different halogen atoms (F, Cl, and Br) were integrated into the COFs framework to optimize the photochemical properties, carrier thermodynamics, and kinetics. The Cl-containing COF TpPaCl achieved the effective co-catalyst-free HER performance under visible light irradiation, resulting in a high HER rate of 16.3 mmol g-1 h-1 in artificial seawater (11.5 mmol g-1 h-1 in real seawater), outperforming that in pure water. The remarkable performance comes from the fine and efficient adjusting of the local environment of the COF framework by the electronegative halogen atoms. Theoretical calculation and soft X-ray absorption spectroscopy (XAS) indicated that the carbon atoms adjacent to the halogen group exhibited strong interaction towards the key intermediate (H*) in the HER process and served as the photoactive H2 evolution sites. The strong polarization derived from the halogen also greatly improves the formation of the long-live electron and accelerates the successive charge transfer. The kinetics were enhanced after salt adsorption in seawater, contributing to the superior HER rate in seawater.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"99 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combating multiple aetiologies of Alzheimer’s disease to rescue behavioural deficits 对抗阿尔茨海默病的多种病因，拯救行为缺陷

IF 8.4 1区化学

Chemical Science Pub Date : 2025-06-06 DOI: 10.1039/d4sc08585j

Madhu Ramesh, Chenikkayala Balachandra, Ashish Kumar, Sourav Samanta, T. Govindaraju

{"title":"Combating multiple aetiologies of Alzheimer’s disease to rescue behavioural deficits","authors":"Madhu Ramesh, Chenikkayala Balachandra, Ashish Kumar, Sourav Samanta, T. Govindaraju","doi":"10.1039/d4sc08585j","DOIUrl":"https://doi.org/10.1039/d4sc08585j","url":null,"abstract":"Alzheimer’s disease (AD) encompass a range of intricate pathologies characterized by aberrant protein aggregation, atypical accumulation of metal ions, increased levels of reactive oxygen species (ROS), oxidative stress, neuroinflammation, and synaptic dysfunction. These collectively contribute to a decline in learning, memory, and cognitive abilities, broadly classified as dementia. AD accounting for most of the dementia cases remains a significant health challenge. Despite extensive research, therapeutic advancements for AD and other neurodegenerative diseases (NDDs) have achieved modest success. In this context, our study presents hybrid drug design approach involving strategic and tactical repurposing of structural and functional pharmacophores of current or failed drugs and biologically active compounds by integrating them in single structural framework to concurrently target key pathological hallmarks viz., amyloid beta (Aβ), tau, metal ions, ROS, and neuroinflammation (NLRP3 inflammasome). The evaluation of in vitro and cellular models of Aβ, tau, and microglia highlights the efficacy of the fluoro-derivative DM4 in mitigating multiple etiological factors. DM4 exhibits excellent blood-brain barrier (BBB) permeability and biocompatibility. DM4 effectively reduced amyloid burden, neuroinflammation, synaptic dysfunction, and neurodegeneration in the APP/PSEN1 transgenic Alzheimer's disease mouse model. Behavioural assessments corroborated the rescue of learning and memory deficits, thereby presenting a viable strategy for the treatment of neurodegeneration and its associated cognitive decline.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"23 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Construction of the reduced nicotinamide adenine dinucleotide salvage pathway in artificial cells and its application in amino acid synthesis 人工细胞中还原性烟酰胺腺嘌呤二核苷酸挽救通路的构建及其在氨基酸合成中的应用

IF 8.4 1区化学

Chemical Science Pub Date : 2025-06-06 DOI: 10.1039/d5sc00852b

Yiming Liu, Shanshan Du, Xiangxiang Zhang, Chao Li, Shubin Li, Wenxia Xu, Jingjing Zhao, Wei Mu, Xiaojun Han

{"title":"Construction of the reduced nicotinamide adenine dinucleotide salvage pathway in artificial cells and its application in amino acid synthesis","authors":"Yiming Liu, Shanshan Du, Xiangxiang Zhang, Chao Li, Shubin Li, Wenxia Xu, Jingjing Zhao, Wei Mu, Xiaojun Han","doi":"10.1039/d5sc00852b","DOIUrl":"https://doi.org/10.1039/d5sc00852b","url":null,"abstract":"Reduced nicotinamide adenine dinucleotide (NADH) salvage pathway reconstitution is a crucial step toward autonomous artificial cells. In living systems, D-ribose is a fundamental precursor intricately involved in the synthesis of nucleotides, nucleic acids, and critical metabolic pathways. An NADH synthesis pathway in artificial cells starting from D-ribose was constructed with five-enzyme cascade containing ribokinase, ribose-phosphate pyrophosphokinase, nicotinamide phosphoribosyltransferase, nicotinamide mononucleotide adenylyltransferase, and formate dehydrogenase (RK, RPPK, NAMPT, NMNAT, and FDH), which efficiently converted 10 mM D-ribose into 415 μM NADH within 80 minutes under optimized conditions. The produced NADH was further used to drive the amino acid metabolism, i.e., to convert NH4+ and α-ketoglutarate to glutamate by introducing additional glutamate dehydrogenase (GDH) inside artificial cells. The successful reconstitution of NADH synthesis pathway lays the foundation for fabricate artificial cells with complicated metabolic net works.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"39 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Intermediate knowledge enhanced the performance of the amide coupling yield prediction model 中间知识增强了酰胺偶联产率预测模型的性能

IF 8.4 1区化学

Chemical Science Pub Date : 2025-06-05 DOI: 10.1039/d5sc03364k

Chonghuan Zhang, Qianghua Lin, Chenxi Yang, Yaxian Kong, Zhunzhun Yu, Kuangbiao Liao

{"title":"Intermediate knowledge enhanced the performance of the amide coupling yield prediction model","authors":"Chonghuan Zhang, Qianghua Lin, Chenxi Yang, Yaxian Kong, Zhunzhun Yu, Kuangbiao Liao","doi":"10.1039/d5sc03364k","DOIUrl":"https://doi.org/10.1039/d5sc03364k","url":null,"abstract":"Amide coupling is an important reaction widely applied in medicinal chemistry. However, condition recommendation remains a challenging issue due to the broad condition space. Recently, accurate condition recommendation via machine learning has emerged as a novel and efficient method to find suitable conditions to achieve the desired transformations. Nonetheless, accurately predicting yields is challenging due to the complex relationships involved. Herein, we present our strategy to address this problem. Two steps were taken to ensure the quality of the dataset. First, we selected a diverse and representative set of substrates to capture a broad spectrum of substrate structures and reaction conditions using an unbiased machine-based sampling approach. Second, experiments were conducted using our in-house high-throughput experimentation (HTE) platform to minimize the influence of human factors. Additionally, we proposed an intermediate knowledge-embedded strategy to enhance the model's robustness. The performance of the model was first evaluated at three different levels—random split, partial substrate novelty, and full substrate novelty. All model metrics in these cases improved dramatically, achieving an R2 of 0.89, MAE of 6.1%, and RMSE of 8.0% in the full substrate novelty test dataset. Moreover, the generalization of our strategy was assessed using external datasets from reported literature, delivering an R2 of 0.71, MAE of 7%, and RMSE of 10%. Meanwhile, the model could recommend suitable conditions for some reactions to elevate the reaction yields. Besides, the model was able to identify which reaction in a reaction pair with a reactivity cliff had a higher yield. In summary, our research demonstrated the feasibility of achieving accurate yield predictions through the combination of HTE and embedding intermediate knowledge into the model. This approach also has the potential to facilitate other related machine learning tasks.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"9 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0