RSC Chemical Biology最新文献

{"title":"Introduction to the themed collection on ‘Molecular and Nanotheranostics’","authors":"Thimmaiah Govindaraju","doi":"10.1039/D3CB90050A","DOIUrl":"10.1039/D3CB90050A","url":null,"abstract":"<p >A graphical abstract is available for this content</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d3cb90050a?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139460546","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}

{"title":"Evaluating Riboglow-FLIM probes for RNA sensing†","authors":"Nadia Sarfraz, Luke K. Shafik, Zachary R. Stickelman, Uma Shankar, Emilia Moscoso and Esther Braselmann","doi":"10.1039/D3CB00197K","DOIUrl":"10.1039/D3CB00197K","url":null,"abstract":"<p >We recently developed Riboglow-FLIM, where we genetically tag and track RNA molecules in live cells through measuring the fluorescence lifetime of a small molecule probe that binds the RNA tag. Here, we systematically and quantitatively evaluated key elements of Riboglow-FLIM that may serve as the foundation for Riboglow-FLIM applications and further tool development efforts. Our investigation focused on measuring changes in fluorescence lifetime of representative Riboglow-FLIM probes with different linkers and fluorophores in different environments. <em>In vitro</em> measurements revealed distinct lifetime differences among the probe variants as a result of different linker designs and fluorophore selections. To expand on the platform's versatility, probes in a wide variety of mammalian cell types were examined using fluorescence lifetime imaging microscopy (FLIM), and possible effects on cell physiology were evaluated by metabolomics. The results demonstrated that variations in lifetime were dependent on both probe and cell type. Interestingly, distinct differences in lifetime values were observed between cell lines, while no overall change in cell health was measured. These findings underscore the importance of probe selection and cellular environment when employing Riboglow-FLIM for RNA detection, serving as a foundation for future tool development and applications across diverse fields and biological systems.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d3cb00197k?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139411255","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}

{"title":"Click chemistry in the development of PROTACs","authors":"Ce Yang, Ravi Tripathi and Binghe Wang","doi":"10.1039/D3CB00199G","DOIUrl":"10.1039/D3CB00199G","url":null,"abstract":"<p >Proteolysis-targeting chimeras or PROTACs are hetero-bifunctional molecules designed to mediate the disposal of a target protein <em>via</em> recruitment of the ubiquitination–proteasome degradation machinery. Because of the chimeric nature of such molecules, their synthesis requires a key step of “assembling” whether in the lab or <em>in situ</em>. Furthermore, targeted PROTACs often are hetero-trifunctional and require a second “assembling” step. Click chemistry has the unique advantages of tethering two or more molecular entities of choice under near physiological conditions and therefore has been applied to the development of PROTACs in various ways. This review provides a succinct summary of this field with a critical analysis of various factors that need to be considered for optimal results. Specifically, we examine issues including applications of click chemistry in <em>in situ</em> assembly for improved delivery, conjugation with a targeting group for selectivity, rapid synthesis for linker optimization, and lysosomal degradation of extracellular and membrane-associated proteins. We also examine reaction kinetics issues whenever possible or warranted.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d3cb00199g?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139064252","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}

{"title":"Engineered triphenylphosphonium-based, mitochondrial-targeted liposomal drug delivery system facilitates cancer cell killing actions of chemotherapeutics†","authors":"Subramaniyam Sivagnanam, Kiran Das, Ieshita Pan, Adele Stewart, Atanu Barik, Biswanath Maity and Priyadip Das","doi":"10.1039/D3CB00219E","DOIUrl":"10.1039/D3CB00219E","url":null,"abstract":"<p >In addition to their classical role in ATP generation, mitochondria also contribute to Ca<small>²⁺</small> buffering, free radical production, and initiation of programmed cell death. Mitochondrial dysfunction has been linked to several leading causes of morbidity and mortality worldwide including neurodegenerative, metabolic, and cardiovascular diseases as well as several cancer subtypes. Thus, there is growing interest in developing drug-delivery vehicles capable of shuttling therapeutics directly to the mitochondria. Here, we functionalized the conventional 10,12-pentacosadiynoic acid/1,2-dimyristoyl-<em>sn-glycero</em>-3-phosphocholine (PCDA/DMPC)-based liposome with a mitochondria-targeting triphenylphosphonium (TPP) cationic group. A fluorescent dansyl dye (DAN) group was also included for tracking mitochondrial drug uptake. The resultant PCDA-TPP and PCDA-DAN conjugates were incorporated into a 1,2-dimyristoyl-<em>sn-glycero</em>-3-phosphocholine (DMPC)-based lipid bilayer, and these modified liposomes (<strong>Lip-DT</strong>) were studied for their cellular toxicity, mitochondrial targeting ability, and efficacy in delivering the drug Doxorubicin (Dox) to human colorectal carcinoma (HCT116) and human breast (MCF7) cancer cells <em>in vitro</em>. This <strong>Lip-DT-Dox</strong> exhibited the ability to shuttle the encapsulated drug to the mitochondria of cancer cells and triggered oxidative stress, mitochondrial dysfunction, and apoptosis. The ability of <strong>Lip-DT-Dox</strong> to trigger cellular toxicity in both HCT116 and MCF7 cancer cells was comparable to the known cell-killing actions of the unencapsulated drug (Dox). The findings in this study reveal a promising approach where conventional liposome-based drug delivery systems can be rendered mitochondria-specific by incorporating well-known mitochondriotropic moieties onto the surface of the liposome.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d3cb00219e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138824135","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}

{"title":"Sialic acids in infection and their potential use in detection and protection against pathogens","authors":"Simone Dedola, Sanaz Ahmadipour, Peterson de Andrade, Alexander N. Baker, Andrew N. Boshra, Simona Chessa, Matthew I. Gibson, Pedro J. Hernando, Irina M. Ivanova, Jessica E. Lloyd, María J. Marín, Alexandra J. Munro-Clark, Giulia Pergolizzi, Sarah-Jane Richards, Iakovia Ttofi, Ben A. Wagstaff and Robert A. Field","doi":"10.1039/D3CB00155E","DOIUrl":"10.1039/D3CB00155E","url":null,"abstract":"<p >In structural terms, the sialic acids are a large family of nine carbon sugars based around an alpha-keto acid core. They are widely spread in nature, where they are often found to be involved in molecular recognition processes, including in development, immunology, health and disease. The prominence of sialic acids in infection is a result of their exposure at the non-reducing terminus of glycans in diverse glycolipids and glycoproteins. Herein, we survey representative aspects of sialic acid structure, recognition and exploitation in relation to infectious diseases, their diagnosis and prevention or treatment. Examples covered span influenza virus and Covid-19, <em>Leishmania</em> and <em>Trypanosoma</em>, algal viruses, <em>Campylobacter</em>, <em>Streptococci</em> and <em>Helicobacter</em>, and commensal <em>Ruminococci</em>.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d3cb00155e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138744630","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}

{"title":"Identifying ligands for the PHD1 finger of KDM5A through high-throughput screening†","authors":"Gloria Ortiz, James E. Longbotham, Sophia L. Qin, Meng Yao Zhang, Gregory M. Lee, R. Jeffrey Neitz, Mark J. S. Kelly, Michelle R. Arkin and Danica Galonić Fujimori","doi":"10.1039/D3CB00214D","DOIUrl":"10.1039/D3CB00214D","url":null,"abstract":"<p >PHD fingers are a type of chromatin reader that primarily recognize chromatin as a function of lysine methylation state. Dysregulated PHD fingers are implicated in various human diseases, including acute myeloid leukemia. Targeting PHD fingers with small molecules is considered challenging as their histone tail binding pockets are often shallow and surface-exposed. The KDM5A PHD1 finger regulates the catalytic activity of KDM5A, an epigenetic enzyme often misregulated in cancers. To identify ligands that disrupt the PHD1-histone peptide interaction, we conducted a high-throughput screen and validated hits by orthogonal methods. We further elucidated structure–activity relationships in two classes of compounds to identify features important for binding. Our investigation offers a starting point for further optimization of small molecule PHD1 ligands.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d3cb00214d?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138715502","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}

{"title":"BrainBike peptidomimetic enables efficient transport of proteins across brain endothelium†","authors":"Maria C. Lucana, Roberta Lucchi, Fabien Gosselet, Cristina Díaz-Perlas and Benjamí Oller-Salvia","doi":"10.1039/D3CB00194F","DOIUrl":"10.1039/D3CB00194F","url":null,"abstract":"<p >Protein therapeutics cannot reach the brain in sufficient amounts because of their low permeability across the blood–brain barrier. Here we report a new family of bicyclic peptide shuttles, BrainBikes, capable of increasing transport of proteins, including antibody derivatives, in a human cell-based model of the blood–brain barrier.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d3cb00194f?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138567586","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}

{"title":"Cationic dextrin nanoparticles for effective intracellular delivery of cytochrome C in cancer therapy†","authors":"Ankita Sarkar, Sanchita Sarkhel, Deepali Bisht and Amit Jaiswal","doi":"10.1039/D3CB00090G","DOIUrl":"10.1039/D3CB00090G","url":null,"abstract":"<p >Intracellular protein delivery shows promise as a selective and specific approach to cancer therapy. However, a major challenge is posed by delivering proteins into the target cells. Despite the development of nanoparticle (NP)-based approaches, a versatile and biocompatible delivery system that can deliver active therapeutic cargo into the cytosol while escaping endosome degradation remains elusive. In order to overcome these challenges, a polymeric nanocarrier was prepared using cationic dextrin (CD), a biocompatible and biodegradable polymer, to encapsulate and deliver cytochrome <em>C</em> (Cyt <em>C</em>), a therapeutic protein. The challenge of endosomal escape of the nanoparticles was addressed by co-delivering the synthesized NP construct with chloroquine, which enhances the endosomal escape of the therapeutic protein. No toxicity was observed for both CD NPs and chloroquine at the concentration tested in this study. Spectroscopic investigations confirmed that the delivered protein, Cyt <em>C</em>, was structurally and functionally active. Additionally, the delivered Cyt <em>C</em> was able to induce apoptosis by causing depolarization of the mitochondrial membrane in HeLa cells, as evidenced by flow cytometry and microscopic observations. Our findings demonstrate that an engineered delivery system using CD NPs is a promising platform in nanomedicine for protein delivery applications.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d3cb00090g?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138519822","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}

{"title":"Bioluminescent detection of viral surface proteins using branched multivalent protein switches†","authors":"Alexander Gräwe, Cindy M. Spruit, Robert P. de Vries and Maarten Merkx","doi":"10.1039/D3CB00164D","DOIUrl":"10.1039/D3CB00164D","url":null,"abstract":"<p >Fast and reliable virus diagnostics is key to prevent the spread of viruses in populations. A hallmark of viruses is the presence of multivalent surface proteins, a property that can be harnessed to control conformational switching in sensor proteins. Here, we introduce a new sensor platform (dark-LUX) for the detection of viral surface proteins consisting of a general bioluminescent framework that can be post-translationally functionalized with separately expressed binding domains. The platform relies on (1) plug-and-play bioconjugation of different binding proteins <em>via</em> SpyTag/SpyCatcher technology to create branched protein structures, (2) an optimized turn-on bioluminescent switch based on complementation of the split-luciferase NanoBiT upon target binding and (3) straightforward exploration of the protein linker space. The influenza A virus (IAV) surface proteins hemagglutinin (HA) and neuraminidase (NA) were used as relevant multivalent targets to establish proof of principle and optimize relevant parameters such as linker properties, choice of target binding domains and the optimal combination of the competing NanoBiT components SmBiT and DarkBiT. The sensor framework allows rapid conjugation and exchange of various binding domains including scFvs, nanobodies and <em>de novo</em> designed binders for a variety of targets, including the construction of a heterobivalent switch that targets the head and stem region of hemagglutinin. The modularity of the platform thus allows straightforward optimization of binding domains and scaffold properties for existing viral targets, and is well suited to quickly adapt bioluminescent sensor proteins to effectively detect newly evolving viral epitopes.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d3cb00164d?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138519823","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}

{"title":"N4-Allylcytidine: a new nucleoside analogue for RNA labelling and chemical sequencing†","authors":"Tengwei Li, Xiao Shu, Minsong Gao, Chenyang Huang, Ting Li, Jie Cao, Xiner Ying, Donghong Liu and Jianzhao Liu","doi":"10.1039/D3CB00189J","DOIUrl":"10.1039/D3CB00189J","url":null,"abstract":"<p >RNA labelling has become indispensable in studying RNA biology. Nucleoside analogues with a chemical sequencing power represent desirable RNA labelling molecules because precise labelling information at base resolution can be obtained. Here, we report a new nucleoside analogue, <em>N</em><small>⁴</small>-allylcytidine (a<small>⁴</small>C), which is able to tag RNA through both <em>in vitro</em> and <em>in vivo</em> pathways and further specifically reacts with iodine to form 3, <em>N</em><small>⁴</small>-cyclized cytidine (cyc-C) in a catalyst-free, fast and complete manner. Full spectroscopic characterization concluded that cyc-C consisted of paired diastereoisomers with opposite chiral carbon centers in the fused 3, <em>N</em><small>⁴</small>-five-membered ring. During RNA reverse transcription into complementary DNA, cyc-C induces base misincorporation due to the disruption of canonical hydrogen bonding by the cyclized structure and thus can be accurately identified by sequencing at single base resolution. With the chemical sequencing rationale of a<small>⁴</small>C, successful applications have been performed including pinpointing <em>N</em><small>⁴</small>-methylcytidine methyltransferases’ substrate modification sites, metabolically labelling mammalian cellular RNAs, and mapping active cellular RNA polymerase locations with the chromatin run-on RNA sequencing technique. Collectively, our work demonstrates that a<small>⁴</small>C is a promising molecule for RNA labelling and chemical sequencing and expands the toolkit for studying sophisticated RNA biology.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d3cb00189j?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138519816","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}