RSC Chemical Biology最新文献

{"title":"Peptides as programmable molecular scaffolds: from chemical synthesis and engineering to translational medicine.","authors":"Shaoren Yuan, Baljit Kaur, Natalie S Fuchs, Sungwoo Cho, Ashraf N Abdo, Moustafa T Gabr","doi":"10.1039/d6cb00117c","DOIUrl":"10.1039/d6cb00117c","url":null,"abstract":"<p><p>Peptides have evolved from naturally occurring ligands and classical hormones into a versatile and engineerable class of functional molecules. This review provides a comprehensive overview of the technological advances that collectively enable programmable peptide engineering across the entire discovery-to-development pipeline. We first discuss innovations in automated flow synthesis, chemoselective ligation, noncanonical residue incorporation, backbone editing, conformational constraint, and late-stage functionalization that have transformed peptide chemistry from linear sequence assembly into a modular engineering scaffold. We then examine modern discovery approaches, including phage display and mRNA display with the RaPID system, along with computational and AI-enabled design strategies that accelerate hit identification and multi-parameter optimization. Biophysical characterization techniques, cellular target engagement assays, and emerging delivery strategies are also reviewed as critical tools for bridging biochemical potency with intracellular activity. Finally, we discuss the translational barriers facing peptide therapeutics and the engineering strategies that have enabled successful clinical applications. Together, these advances establish a new era in which peptides are no longer viewed as inherently labile biomolecules but as chemically programmable scaffolds whose structures and functions can be precisely engineered.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1237-1252"},"PeriodicalIF":3.9,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13246153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148212852","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":"Understanding insulin-like peptide 5 (INSL5) and relaxin family peptide receptor 4 (RXFP4): structure, signalling, and function.","authors":"Hongkang Wu, Huahao Wang, Isabelle Riches, Ivan Maslov, Predrag Kalaba, Myat Noe Han, Ruslan Pustovit, John B Furness, Ross A D Bathgate, Mohammed Akhter Hossain","doi":"10.1039/d6cb00102e","DOIUrl":"10.1039/d6cb00102e","url":null,"abstract":"<p><p>Insulin-like peptide 5 (INSL5) is a member of the relaxin/insulin peptide family, predominantly produced by enteroendocrine L cells in the distal gut. Although initially characterised based on its structural similarity to insulin and relaxin peptides, INSL5 is now increasingly recognised as an important regulator of gastrointestinal physiology. Its endogenous receptor, relaxin family peptide receptor 4 (RXFP4), is primarily expressed in the gastrointestinal tract and signals mainly through G_i proteins. Recent studies have provided compelling evidence that the INSL5-RXFP4 signalling axis is an important regulator of colonic motility. In this review, we summarise current knowledge of the structure-function relationships of INSL5 and RXFP4, advances in the design of INSL5 analogues, and the signalling mechanisms underlying receptor activation. We also discuss the physiological and pharmacological evidence supporting a role for INSL5-RXFP4 signalling in colonic motility and highlight opportunities for the development of chemical probes and therapeutic leads targeting this system for the treatment of chronic constipation.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1221-1236"},"PeriodicalIF":3.9,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13234771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148200575","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":"Recent progress in cGAS-STING agonist design and mechanisms of cancer immune modulation.","authors":"Liao Wang, Muhammad Nafees, He Fei, Muhammad Hanif, Piaoping Yang","doi":"10.1039/d6cb00005c","DOIUrl":"10.1039/d6cb00005c","url":null,"abstract":"<p><p>The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway is a crucial modulator of innate immunity and an important target for next-generation cancer immunotherapy. Numerous cGAS-STING agonists have been developed and evaluated for their ability to promote anti-tumour immune responses. Cyclic dinucleotides (CDNs) are the most widely employed natural STING agonists; however, poor membrane permeability and enzymatic instability have motivated the development of non-CDN small-molecule agonists, including organic scaffolds and metal-based complexes with improved stability and tunable physicochemical properties. Additionally, nanomaterials that incorporate metal complexes with or without STING agonists have recently emerged as promising platforms for achieving robust therapeutic effects, facilitating targeted delivery, controlled release, and integration with other treatment modalities such as photodynamic therapy. This review offers a comprehensive examination of advancements over the past two years in the design and development of STING modulators, including organic scaffolds, metal-based complexes, and nanomaterials that encapsulate or tether metal-based drugs. It emphasises their chemical structures and the molecular mechanisms that facilitate STING activation and discusses significant challenges while delineating future research and therapeutic development directions.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1167-1191"},"PeriodicalIF":3.9,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13193615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148018030","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":"Cooperative membrane association as a mechanistic origin of synergistic antimicrobial peptide activity.","authors":"Angela Medvedeva, Anatoly B Kolomeisky","doi":"10.1039/d6cb00084c","DOIUrl":"10.1039/d6cb00084c","url":null,"abstract":"<p><p>Antimicrobial peptides (AMPs) are central components of the innate immunity system that can be found in almost all living organisms. They are promising alternatives to conventional antibiotics due to their broad-spectrum activity and reduced susceptibility to resistance. Experimental studies have shown that combinations of AMPs can act synergistically, achieving enhanced antibacterial efficacy at lower total concentrations in combination than individually. However, despite its prevalence, AMP synergy has until recently been lacking a unifying mechanistic and predictive framework. In this review, we combine the latest theoretical, computational, and experimental advances to present a novel quantitative framework that views AMP synergy as a consequence of cooperative membrane association. Chemical-kinetic models of AMPs association to bacterial membranes show that favorable intermolecular interactions between different AMP species accelerate their binding, enhancing antibacterial activity. Within this framework, an effective interaction parameter, Δ<i>E</i>, emerges as a quantitative descriptor of cooperativity linking microscopic interactions to macroscopic synergy metrics such as minimal inhibitory concentrations (MIC). Extensions of this approach rationalize the enhanced efficacy of heterogeneous multi-AMP mixtures and clarify the specific case of AMPs associating to each other as hetero-oligomers before binding to the bacterial membranes. Complementary statistical and machine-learning analyses further demonstrate that synergistic AMP combinations are characterized by physicochemical complementarity rather than similarity, enabling prediction of synergy from sequence-derived features. The review demonstrates that AMP synergy can be quantitatively described and potentially rationally designed using a combined chemical-kinetic and statistical machine-learning approach, providing a foundation for systematic development of effective and resistance-resilient multi-AMP therapeutics.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1253-1264"},"PeriodicalIF":3.9,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13223778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148151761","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":"Application of the YebF secretion pathway in <i>Escherichia coli</i> for rapid, on-plate screening of PETase libraries for improved activity.","authors":"Jaeick Lee, Maame Yaa Yamoa, Celina L Bradley, Graeme Howe, David L Zechel","doi":"10.1039/d6cb00090h","DOIUrl":"10.1039/d6cb00090h","url":null,"abstract":"<p><p>Plastic waste such as polyethylene terephthalate (PET) is a major environmental burden, and enzymes capable of degrading PET are emerging as biocatalytic tools for sustainable recycling. Progress in improving PET hydrolases (or PETases) has been constrained by the lack of simple and reliable screening systems. Here, we report a functional screen for PETase activity in <i>Escherichia coli</i> based on a zone-clearing assay, where the YebF secretory pathway is used to secrete YebF-PETase onto agar plates supplemented with bis(2-hydroxyethyl) terephthalate (BHET). Enzyme activity is observed as zones of clearance around <i>E. coli</i> colonies that express active YebF-PETases, as insoluble BHET is converted to soluble products. As proof of concept, the screen was used to evaluated libraries of YebF-leaf-branch compost cutinase (LCC) generated by site-saturation mutagenesis at the active site residues Y95, L102, and V212. This led to the identification of the more active LCC variants V212T and L102F-V212T. The secretion-based assay was then validated using turbidity assays and untagged LCC variants, where the L102F-V212T variant was confirmed to be more active against PET than the wild-type enzyme. Docking simulations indicated that V212T improves substrate positioning in the active site while L102F modifies surface charge and hydrophobicity, potentially enhancing binding to the hydrophobic substrate. Overall, the YebF secretion-driven functional screen serves as a straightforward platform for identifying improved PETase variants and potentially other plastic degrading enzymes.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1359-1371"},"PeriodicalIF":3.9,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13205129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044040","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":"Let the peptides shine: SOX (Sulfonamido-OXine)-labelled peptides for direct kinase and phosphatase monitoring.","authors":"Lydia E Papagora, Stephen A Cochrane","doi":"10.1039/d6cb00048g","DOIUrl":"10.1039/d6cb00048g","url":null,"abstract":"<p><p>Protein kinases and their cognate phosphatases are central regulators of cellular signalling, acting through the opposing processes of phosphorylation and dephosphorylation. Defects in kinase/phosphatase signalling are implicated in many diseases, including cancer, neurodegenerative conditions and metabolic disorders. Rapid and economical methods for measuring kinase activities are critically needed as diagnostic tools and for the evaluation of kinase inhibitors, including approaches that allow direct and quantitative measurement of kinase activities in complex media like cell lysates. SOX (sulfonamido-oxine)-labelled peptides, that upon phosphorylation chelate Mg²⁺ and undergo Chelation-Enhanced Fluorescence (CHEF), have emerged as a convenient class of modular kinase sensors. The development of an array of SOX-peptides has allowed researchers to gain insights into biological processes including binding events, conformational constraints, enzyme activities, protein trafficking and localization. This focused review provides an overview of the use of SOX-labelled peptides for probing kinase and phosphatase activity in real-time assays, including their development, synthesis, applications and strengths and weaknesses compared to other kinase assays.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1209-1220"},"PeriodicalIF":3.9,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13210295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044048","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":"The position of hydrophobic residues impacts cellular uptake and intracellular localization of cell penetrating peptides.","authors":"Adeline Schmitt, Helma Wennemers","doi":"10.1039/d6cb00107f","DOIUrl":"10.1039/d6cb00107f","url":null,"abstract":"<p><p>Cell-penetrating peptides (CPPs) are widely used to deliver cargo into mammalian cells, yet efficient cellular uptake and endosomal escape remain key challenges. In this study, we evaluated how hydrophobic (4<i>S</i>)-4-cyclohexylproline (ChPro) residues and their spatial arrangement influence cellular uptake, endosomal escape, and subcellular distribution of conformationally constrained cationic peptides consisting of (4<i>S</i>)-guanidiniumproline (Gup). The evaluation revealed a greater effect on uptake and endosomal escape by positioning the hydrophobic block at the C- rather than the N-terminus. The amphipathic peptides with a C-terminal (ChPro)₃ sequence accumulated in mitochondria and the endoplasmic reticulum. These insights are relevant for optimizing cellular uptake, intracellular localization, and endosomal escape of CPPs.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1352-1358"},"PeriodicalIF":3.9,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13232632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148164979","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":"Scarless one-tube genome assembly <i>via</i> computationally optimized uracil-DNA glycosylase reactions.","authors":"Rachel M Carson, Patrick M Needham, Pedro J Fernandez Mendoza, Sam R Nugen","doi":"10.1039/d5cb00317b","DOIUrl":"10.1039/d5cb00317b","url":null,"abstract":"<p><p>Synthetic biology enables the creation of systems such as bacteriophage (phage)-based biosensors, leveraging the innate specificity and efficiency of phages to rapidly identify pathogens. However, the current genome assembly and editing methods, including Gibson Assembly, Golden Gate Assembly, and CRISPR-Cas systems, have limitations that can hinder speed and flexibility, especially when complex modifications are needed. This study introduces a novel means for generating engineered bacteriophages through a one-pot, modular <i>in vitro</i> genome assembly platform utilizing uracil-DNA glycosylase, which allows genome modification without requiring extended overlaps, the removal of restriction enzyme sites, a Cas system, or homologous recombination. The design also minimizes the risk of secondary structure formation (<i>e.g.</i>, hairpins), allowing for a more efficient assembly of fragments. To demonstrate functional genome engineering, we incorporated a NanoLuc luciferase reporter gene into the T7 genome, producing a recombinant phage capable of detecting <i>E. coli</i>, a strategy consistent with our previous work on waterborne pathogen detection. This platform enables rapid and flexible synthetic genome construction with high functional assembly efficiency, with broad applications in phage engineering, biosensing, and synthetic biology.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1389-1401"},"PeriodicalIF":3.9,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13227401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148158501","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":"ortho-Substituents govern aryl aldehyde reactivity: toward lysine-targeted, tunable inhibitors of glucose-6-phosphate dehydrogenase","authors":"Bronwyn E. Rowland, Kelsey D. Roy, Adil Alkaş, Mirele Barsoum, Tangweth Kuot, Jesse C. Fuller, Adrien J. Naudet, Elisa Ospanow and David L. Jakeman","doi":"10.1039/D6CB00070C","DOIUrl":"10.1039/D6CB00070C","url":null,"abstract":"<p >Certain drugs achieve highly potent and long-lasting enzyme inhibition by forming covalent bonds with nucleophilic amino acid functionalities. Aldehyde-containing inhibitors are able to react with lysine ε-amino functionalities to form reversible-covalent imine (Schiff base) adducts. <em>ortho</em>-Substituted aryl aldehydes have been used to further stabilize these imines through intramolecular interactions. However, relationships between aryl aldehyde structure, reactivity, and enzyme inhibition remain poorly defined. To address this gap, we characterized imine formation across a diverse panel of aryl aldehydes in aqueous solution and tested whether reactivity trends will predict covalent inhibition mechanisms. First, we assessed imine yield, reaction rate, and apparent binding affinity by NMR and UV-vis spectroscopy using a lysine surrogate. We then evaluated inhibitory activity against an enzyme using dose–response and dilution assays to determine potency and reversibility. <em>Leuconostoc mesenteroides</em> glucose-6-phosphate dehydrogenase (G6PD), which contains a lysine-rich active site, served as the enzyme model. The reactivity of aryl aldehydes in our panel was primarily governed by <em>ortho</em>-substituents, particularly their ability to stabilize the imine and coordinate the reacting partners. Reactivity generally correlated with inhibitor potency, but not with reversibility. We also identified previously unreported aryl aldehyde G6PD inhibitors bearing boronic acid, ethynyl, and phosphonate substituents, spanning irreversible-covalent, reversible-covalent, and rapid-equilibrium inhibition mechanisms. These findings establish structure–reactivity–activity relationships for aryl aldehydes and demonstrate their potential for tunability in rational inhibitor design. Collectively, this work strengthens the foundation for lysine-targeted covalent inhibitor development.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 6","pages":" 1073-1087"},"PeriodicalIF":3.1,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13189197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147989472","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":"The working lives of neuronal 5-HT_2A receptors from the outside in.","authors":"Aneesah Jabar, Mikayla Pinto, Terence E Hébert","doi":"10.1039/d6cb00014b","DOIUrl":"10.1039/d6cb00014b","url":null,"abstract":"<p><p>5-HT_2A receptors have been shown to play critical roles in regulating neuronal signalling networks and brain plasticity. They have become important targets for treatment of resistant forms of mental health disorders such as depression, anxiety and post-traumatic stress disorder. Like many G protein-coupled receptors (GPCRs), signalling downstream of 5-HT_2A depends on where the receptor is in the cell. Events and signalling pathways modulated by the cell surface pool of receptors may be distinct from those regulated by an internal pool of receptors. In this review, we parse out how the cell organizes and regulates this location bias and explore approaches to target the distinct receptor pools pharmacologically.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1192-1208"},"PeriodicalIF":3.9,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13209151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044103","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}