RSC Chemical Biology最新文献

Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK/Tec double deficient X-linked agammaglobulinemia model.

IF 4.2

RSC Chemical Biology Pub Date : 2025-03-31 DOI: 10.1039/d4cb00312h

Burcu Bestas, H Yesid Estupiñán, Qing Wang, Shabnam Kharazi, Chenfei He, Dara K Mohammad, Dhanu Gupta, Oscar P B Wiklander, Taavi Lehto, Karin E Lundin, Anna Berglöf, Mikael C I Karlsson, Frank Abendroth, Samir El Andaloussi, Michael J Gait, Matthew J A Wood, Christian J Leumann, Dmitry A Stetsenko, Robert Månsson, Jesper Wengel, Rula Zain, C I Edvard Smith

{"title":"Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK/Tec double deficient X-linked agammaglobulinemia model.","authors":"Burcu Bestas, H Yesid Estupiñán, Qing Wang, Shabnam Kharazi, Chenfei He, Dara K Mohammad, Dhanu Gupta, Oscar P B Wiklander, Taavi Lehto, Karin E Lundin, Anna Berglöf, Mikael C I Karlsson, Frank Abendroth, Samir El Andaloussi, Michael J Gait, Matthew J A Wood, Christian J Leumann, Dmitry A Stetsenko, Robert Månsson, Jesper Wengel, Rula Zain, C I Edvard Smith","doi":"10.1039/d4cb00312h","DOIUrl":"10.1039/d4cb00312h","url":null,"abstract":"Splice-switching oligonucleotides (SSOs) have been developed as a treatment for various disorders, including Duchenne muscular dystrophy and spinal muscular atrophy. Here, the activity of several different SSOs was investigated as potential treatments for B lymphocyte disorders with a focus on X-linked agammaglobulinemia (XLA), caused by defects in the gene encoding Bruton's tyrosine kinase (BTK). In this study, the activity of locked nucleic acid (LNA), tricyclo-DNA (tcDNA), phosphoryl guanidine oligonucleotides (PGO) and phosphorodiamidate morpholino oligomers (PMO) were compared, targeting the pseudoexon region of BTK pre-mRNA. We further investigated the effect of conjugating cell-penetrating peptides, including Pip6a, to the SSOs. The effect was measured as splice-switching in vitro as well as in a further developed, bacterial artificial chromosome transgenic mouse model of XLA. Therapy in the form of intravenous infusions 2 times a week during 3 weeks of PMO oligomers conjugated to Pip6a was sufficient to partly restore the in vivo B lineage phenotype. SSOs treatment also provides a unique opportunity to get insights into a restoration process, when B lymphocytes of different maturation stages are simultaneously splice-corrected.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11955834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

3'-O-β-Glucosylation of nucleoside analogues using a promiscuous bacterial glycosyltransferase.

IF 4.2

RSC Chemical Biology Pub Date : 2025-03-25 DOI: 10.1039/d5cb00026b

Jonathan P Dolan, Tessa Keenan, Aisling Ní Cheallaigh, Martin A Fascione, Gavin J Miller

引用次数: 0

Synthetic biology routes to new and extinct natural products.

IF 4.2

RSC Chemical Biology Pub Date : 2025-03-21 DOI: 10.1039/d5cb00047e

Thomas J Simpson

{"title":"Synthetic biology routes to new and extinct natural products.","authors":"Thomas J Simpson","doi":"10.1039/d5cb00047e","DOIUrl":"10.1039/d5cb00047e","url":null,"abstract":"Recent developments in genome sequencing and genetic engineering have revolutionised elucidation of biosynthetic pathways in bacteria and fungi and allowed production of new natural products and engineered strains with optimised production of new and/or preferred metabolites. The clinically important antibiotic mupirocin is a mixture of closely related pseudomonic acids produced by Pseudomonas fluorescens via a trans-AT modular PKS. Extensive gene knock-out experiments have led to the isolation of a plethora of new metabolites: both biosynthetic intermediates and shunt products. Parallel experiments, along with swapping of biosynthetic genes, with a Pseudoalteromonas sp. which produces the closely related thiomarinols give similar results and many new products. A genetically engineered strain of P. fluorescens produces high titres of a single pseudomonic acid with improved stability and antibiotic properties. Tenellin and bassianin are insecticidal fungal metabolites produced by Beauvaria species via multi-domain PKS-NRPSs. Heterologous expression in Aspergillus oryzae of hybrid systems produced by domain swapping between the two biosynthetic gene clusters produce many new metabolites in high yields and reveal the key elements in control of polyketide chain length and methylation, showing the potential for combinatorial biosynthesis of these and related metabolites. Cryptosporiopsis sp. 8999 produces three related dimeric xanthones. Gene knock-outs allow elucidation of the full biosynthetic pathway, isolation of the monomeric precursor and engineering of a strain producing only the major component of the wild-type mixture.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thiophosphate bioisosteres of inositol hexakisphosphate enhance binding affinity and residence time on bacterial virulence factors.

IF 4.2

RSC Chemical Biology Pub Date : 2025-03-20 DOI: 10.1039/d4cb00228h

Rebecca Cummer, Garvit Bhatt, Lauren M Finn, Bettina G Keller, Bhushan Nagar, Bastien Castagner

{"title":"Thiophosphate bioisosteres of inositol hexakisphosphate enhance binding affinity and residence time on bacterial virulence factors.","authors":"Rebecca Cummer, Garvit Bhatt, Lauren M Finn, Bettina G Keller, Bhushan Nagar, Bastien Castagner","doi":"10.1039/d4cb00228h","DOIUrl":"10.1039/d4cb00228h","url":null,"abstract":"Inositol phosphates are essential for mammalian cell signalling with critical roles in cellular processes. The fully phosphorylated inositol phosphate, myo-inositol hexakisphosphate (IP6), modulates numerous eukaryotic proteins and bacterial virulence factors. It has been suggested that the high charge density of IP6 causes restructuring of virulence factors in mammalian cells, activating their enzymatic activity. IP6 is challenging to study due to its phytase instability and propensity to precipitate. Here we suggest that the thiophosphate bioisostere, myo-inositol hexakisthiophosphate (IT6), will mitigate these issues, as thiophosphate substitution has been found to be phytase resistant and improve solubility. Assessment of the chemical properties of IT6 has indeed validated these characteristics. In addition, we performed biophysical characterization of IT6 binding to the virulence factors Salmonella enterica serovar Typhimurium AvrA, Vibrio parahaemolyticus VopA, and Clostridioides difficile TcdB. Our data show that the higher charge density of IT6 increased its binding affinity and residence time on the proteins, which improved stabilization of the bound-state. IT6 is a valuable tool for structural biology research and the described biophysical characteristics of thiophosphate substitution are of value in medicinal chemistry.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Peptide-mediated display of Tau-derived peptide for construction of microtubule superstructures.

IF 4.2

RSC Chemical Biology Pub Date : 2025-03-19 DOI: 10.1039/d4cb00290c

Hiroshi Inaba, Daichi Kageyama, Soei Watari, Mahoko Tateishi, Akira Kakugo, Kazunori Matsuura

{"title":"Peptide-mediated display of Tau-derived peptide for construction of microtubule superstructures.","authors":"Hiroshi Inaba, Daichi Kageyama, Soei Watari, Mahoko Tateishi, Akira Kakugo, Kazunori Matsuura","doi":"10.1039/d4cb00290c","DOIUrl":"10.1039/d4cb00290c","url":null,"abstract":"Microtubules are major cytoskeletons involved in various cellular functions, such as regulating cell shape and division and cargo transport via motor proteins. In addition to widely studied singlet microtubules, complex microtubule superstructures, including doublets and bundles, provide unique mechanical and functional properties in vivo. However, a method to construct such superstructures in vitro remains unresolved. This study presents a peptide-based approach for constructing microtubule superstructures by displaying Tau-derived peptides (TP) on the outer surface of microtubules using KA7 peptides as binding units. The KA7-connected TP (KA7-TP) bound to the C-terminal tail on the outer surface of microtubules and induced doublets and bundles by recruiting tubulin. Notably, the outer layers of the doublet microtubules generated by KA7-TP dissociated, highlighting the utility of this approach for studying the formation/dissociation mechanisms of microtubule superstructures. The simple peptide-based approach facilitates our understanding of microtubule superstructures and offers new opportunities for applying microtubule superstructures to nanotechnology.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epichaperomes: redefining chaperone biology and therapeutic strategies in complex diseases.

IF 4.2

RSC Chemical Biology Pub Date : 2025-03-19 DOI: 10.1039/d5cb00010f

Chiranjeevi Pasala, Chander S Digwal, Sahil Sharma, Shujuan Wang, Alessia Bubula, Gabriela Chiosis

{"title":"Epichaperomes: redefining chaperone biology and therapeutic strategies in complex diseases.","authors":"Chiranjeevi Pasala, Chander S Digwal, Sahil Sharma, Shujuan Wang, Alessia Bubula, Gabriela Chiosis","doi":"10.1039/d5cb00010f","DOIUrl":"10.1039/d5cb00010f","url":null,"abstract":"The complexity of disease biology extends beyond mutations or overexpression, encompassing stress-induced mechanisms that reshape proteins into pathological assemblies. Epichaperomes, stable and disease-specific assemblies of chaperones and co-chaperones, exemplify this phenomenon. This review emphasizes the critical structural and functional distinctions between epichaperomes and canonical chaperones, highlighting their role in redefining therapeutic strategies. Epichaperomes arise under stress conditions through post-translational modifications that stabilize these assemblies, enabling them to act as scaffolding platforms that rewire protein-protein interaction networks and drive the pathological phenotypes of complex diseases such as cancer and neurodegeneration. Chemical biology has been instrumental in uncovering the unique nature of epichaperomes, with small molecules like PU-H71 elucidating their biology and demonstrating their therapeutic potential by dismantling pathological scaffolds and restoring normal protein-protein interaction networks. By targeting epichaperomes, we unlock the potential for network-level interventions and personalized medicine, offering transformative possibilities for diseases driven by protein-protein interaction network dysregulation.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of a fluorescence-based assay for RecBCD activity using functional data analysis and design of experiments.

IF 4.2

RSC Chemical Biology Pub Date : 2025-03-17 DOI: 10.1039/d4cb00291a

Adam Winnifrith, Steven R Brown, Piotr Jedryszek, C Grant, Philip E Kay, Adam M Thomas, Jacob D Bradbury, Thomas Lanyon-Hogg

{"title":"Development of a fluorescence-based assay for RecBCD activity using functional data analysis and design of experiments.","authors":"Adam Winnifrith, Steven R Brown, Piotr Jedryszek, C Grant, Philip E Kay, Adam M Thomas, Jacob D Bradbury, Thomas Lanyon-Hogg","doi":"10.1039/d4cb00291a","DOIUrl":"10.1039/d4cb00291a","url":null,"abstract":"Biochemical assays are essential tools in biological research and drug discovery, but optimisation of these assays is often a challenging and lengthy process due to the wide range of input variables and the complex effects of these variables on one another. Traditional 'one-factor-at-a-time' optimisation is both time-consuming and fails to explore the full range of input combinations. In contrast, the modern 'design of experiments' (DoE) approach enables simultaneous investigation of multiple input variables and their interactions, leading to more information-rich and efficient experimentation. We therefore sought to apply DoE to the optimisation of a new fluorescence-based assay for the enzyme RecBCD, a helicase-nuclease-ATPase complex involved in bacterial stress responses. A novel 'functional data analysis' (FDA) approach was used to predict the shape of RecBCD reaction curves in response to different combinations of input variables, which successfully identified assay conditions suitable for drug screening. Collectively, this work delivers a new assay for the antibiotic target RecBCD and demonstrates the potential of DoE and FDA to accelerate biochemical assay development.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11955833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Real-time bioluminescence imaging of nitroreductase in breast cancer bone metastasis.

IF 4.2

RSC Chemical Biology Pub Date : 2025-03-14 DOI: 10.1039/d4cb00310a

Kang Lu, Mengxi Zhang, Zuotong Tian, Han Xiao

{"title":"Real-time bioluminescence imaging of nitroreductase in breast cancer bone metastasis.","authors":"Kang Lu, Mengxi Zhang, Zuotong Tian, Han Xiao","doi":"10.1039/d4cb00310a","DOIUrl":"10.1039/d4cb00310a","url":null,"abstract":"Bone metastasis is a leading cause of mortality in breast cancer patients. Monitoring biomarkers for bone metastasis in breast cancer is crucial for the development of effective interventional treatments. Despite being a highly vascularized tissue, the bone presents a particularly hypoxic environment. Tumor hypoxia is closely linked to increased levels of various reductases, including nitroreductase (NTR). Currently, there are few probes available to detect NTR levels in breast cancer bone metastases. Although bioluminescent imaging is promising due to its specificity and high signal-to-noise ratio, many probes face challenges such as short emission wavelengths, reliance on complex conditions like external adenosine triphosphate, or lack of tissue specificity. In this study, through \"caging\" the luciferase substrate with an NTR-responsive aromatic nitro recognition group, we developed a highly sensitive and selective NTR-sensitive bioluminescent probe. The resulting probe effectively detects NTR in breast cancer cells and enables real-time monitoring of NTR in a mouse model of breast cancer bone metastasis. Additionally, it can differentiate between primary and bone tumors, and allow continuous monitoring of NTR levels, thus providing valuable insights into bone tumor progression. This work provides a powerful tool for further understanding the biological functions of NTR in breast cancer bone metastasis.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of water in mediating DNA structures with epigenetic modifications, higher-order conformations and drug-DNA interactions.

IF 4.2

RSC Chemical Biology Pub Date : 2025-03-14 DOI: 10.1039/d4cb00308j

Roshan Satange, Ming-Hon Hou

引用次数: 0

Ganglioside lipids inhibit the aggregation of the Alzheimer's amyloid-β peptide.

IF 4.2

RSC Chemical Biology Pub Date : 2025-03-13 DOI: 10.1039/d4cb00189c

Zenon Toprakcioglu, Akhila K Jayaram, Tuomas P J Knowles

{"title":"Ganglioside lipids inhibit the aggregation of the Alzheimer's amyloid-β peptide.","authors":"Zenon Toprakcioglu, Akhila K Jayaram, Tuomas P J Knowles","doi":"10.1039/d4cb00189c","DOIUrl":"10.1039/d4cb00189c","url":null,"abstract":"The aggregation of the amyloid-β (Aβ) peptides (Aβ42/Aβ40) into amyloid fibrils and plaques is one of the molecular hallmarks in dementia and Alzheimer's disease (AD). While the molecular mechanisms behind this aggregation process are not fully known, it has been shown that some biomolecules can accelerate this process whereas others can inhibit amyloid formation. Lipids, which are ubiquitously found in cell membranes, play a pivotal role in protein aggregation. Here, we investigate how ganglioside lipids, which are abundant in the brain and in neurons, can influence the aggregation kinetics of both Aβ42 and Aβ40. We employ a variety of biophysical assays to characterise the effect ganglioside lipids have on the aggregation of Aβ. Through kinetic analysis, we show that the primary nucleation rate is greatly affected by the addition of gangliosides and that these lipids impair Aβ42 aggregation, while completely inhibiting Aβ40 aggregation. Furthermore, we find that an Aβ-ganglioside complex is formed, which potentially disrupts the aggregation pathway and results in delayed kinetics. Taken together, our results provide a quantitative description of how lipid molecules such as gangliosides can inhibit the aggregation of Aβ and shed light on the key factors that control these processes. In view of the fact that declining levels of gangliosides in neurons have been associated with ageing, our findings could be instrumental towards establishing new approaches in the prevention of amyloid-β aggregation.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0