RSC Chemical Biology最新文献_第4页

ΔAlaAz cleavable linkers: efficient peptide cleavage in the presence of aromatic thiols and air oxygen. ΔAlaAz可切割连接剂：在芳香硫醇和空气氧的存在下，有效的肽切割。

IF 3.9

RSC Chemical Biology Pub Date : 2026-08-12 eCollection Date: 2026-10-08 DOI: 10.1039/d6cb00161k

Wai-Lun Chan, Alexander A Vinogradov

引用次数: 0

Disulfide rebridging platforms for site-specific ADC conjugation. 特异位点ADC偶联的二硫重桥平台。

IF 3.9

RSC Chemical Biology Pub Date : 2026-08-11 eCollection Date: 2026-10-08 DOI: 10.1039/d6cb00121a

László Petri, Írisz K Kovács, Blanka J Kiss, György M Keserű

{"title":"Disulfide rebridging platforms for site-specific ADC conjugation.","authors":"László Petri, Írisz K Kovács, Blanka J Kiss, György M Keserű","doi":"10.1039/d6cb00121a","DOIUrl":"10.1039/d6cb00121a","url":null,"abstract":"Antibody-drug conjugates (ADCs) have emerged as a transformative class of targeted therapeutics, combining the exquisite specificity of monoclonal antibodies with the potency of small-molecule cytotoxic payloads. While numerous strategies exist to generate ADCs, site-specific conjugation methods have gained prominence due to their ability to produce homogeneous constructs with defined drug-antibody ratios, improved stability, and predictable pharmacokinetics. Among these, disulfide rebridging chemistries have recently attracted considerable attention as an elegant and versatile platform for precise antibody modification. By exploiting native interchain disulfide bonds, rebridging approaches restore structural integrity while introducing functional handles for payload attachment, enabling the generation of reproducible and structurally well-defined ADCs from native antibodies. This review provides a systematic and comprehensive overview of the chemical methodologies developed for disulfide rebridging, tracing the evolution of rebridging reagents and strategies from early maleimide and bissulfone scaffolds to modern dibromopyridazinediones, and other bridging frameworks. Beyond chemistry, we discuss the biological implications of rebridged ADCs, including their translational potential, supported by emerging preclinical and clinical data. Providing a dual chemical and biological perspective, this review aims to serve as a practical guide for researchers seeking to navigate the expanding landscape of site-specific ADC development, ultimately contributing to the rational design of next-generation targeted therapeutics.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1943-1957"},"PeriodicalIF":3.9,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13482864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148799020","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

Synthesis of a guanylylated peptide derived from norovirus VPg as a molecular tool for studying norovirus replication. 从诺如病毒VPg衍生的一种鸟苷化肽的合成，作为研究诺如病毒复制的分子工具。

IF 3.9

RSC Chemical Biology Pub Date : 2026-08-10 eCollection Date: 2026-10-08 DOI: 10.1039/d6cb00092d

Bob van Puffelen, Leandro Xavier Neves, Roy Steneker, Nico J Meeuwenoord, Edward Emmott, Dmitri V Filippov

{"title":"Synthesis of a guanylylated peptide derived from norovirus VPg as a molecular tool for studying norovirus replication.","authors":"Bob van Puffelen, Leandro Xavier Neves, Roy Steneker, Nico J Meeuwenoord, Edward Emmott, Dmitri V Filippov","doi":"10.1039/d6cb00092d","DOIUrl":"10.1039/d6cb00092d","url":null,"abstract":"Norovirus is a leading cause of global acute gastroenteritis, yet the mechanisms underlying its replication remain incompletely understood. As a positive-sense single-stranded RNA (+ ssRNA) virus, norovirus utilizes a nucleotidylated viral protein (VPg) as a primer for synthesis of its genomic and subgenomic mRNAs. In this study, we report the efficient solid-phase synthesis of a guanylylated (also known as GMPylated) VPg-derived peptide fragment using a novel pre-guanylylated tyrosine building block equipped with acid-sensitive protecting groups. This approach enables a streamlined, one-step deprotection and cleavage process. The resulting synthetic peptide was characterised via LC-MS/MS, establishing its gas-phase fragmentation behaviour and confirming prior observations of a diagnostic guanine nucleobase peak at 152.0572 m/z. We subsequently applied these findings to develop a parallel reaction monitoring (PRM) assay to investigate endogenous VPg guanylylation in murine microglial cells infected with murine norovirus (MNV). Our results demonstrate that while unmodified VPg is detectable from 4 hours post-infection, the guanylylated form appears predominantly during later stages (8-12 hpi). The timing of VPg guanylylation is consistent with a model where guanylylation may serve as a regulator in the switch between anti-sense and sense RNA synthesis, though at this time this hypothesis is speculative and remains to be proven. These synthetic molecular tools and mass spectrometry assays provide a robust framework for further exploring the role of nucleotidylation in viral pathogenesis and in broader cell and pathogen biology.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1978-1985"},"PeriodicalIF":3.9,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13485141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798950","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

Current landscape of RNA chemistry and delivery in cancer immunotherapy. RNA化学和递送在癌症免疫治疗中的现状。

IF 3.9

RSC Chemical Biology Pub Date : 2026-08-08 eCollection Date: 2026-10-08 DOI: 10.1039/d6cb00037a

Hayden Tobias, Sarah Porter, Isabella Marcelo, Abigail Koons, Soren C Spina, Courtney Culkins, Blaise R Kimmel

{"title":"Current landscape of RNA chemistry and delivery in cancer immunotherapy.","authors":"Hayden Tobias, Sarah Porter, Isabella Marcelo, Abigail Koons, Soren C Spina, Courtney Culkins, Blaise R Kimmel","doi":"10.1039/d6cb00037a","DOIUrl":"10.1039/d6cb00037a","url":null,"abstract":"Small interfering RNAs (siRNAs) are programmable nucleic acids that play key roles in chemical biology and can selectively silence disease-associated genes through RNA interference (RNAi). These programmable nucleic acids have emerged as a powerful class of medicines and chemical biology tools that can rewire tumor-immune signaling, target immunosuppressive genes, stimulate immune responses, and boost the immune system against immune-mediated diseases. Recent success in the rapid synthesis and applications of siRNA highlights the potential of this technology to address previously \"undruggable\" targets across a range of genetic, metabolic, and oncologic diseases. Despite the potential of these siRNA-based therapies, including those used in cancer immunotherapy, challenges such as off-target effects during delivery, chemical degradation of siRNA in the body, and immunogenicity limit their efficacy. This review provides a comprehensive overview of the chemical biology and chemical modifications inherent to the design of robust siRNA therapies; the nucleic acid structure-function relationships that dictate the cellular mechanisms underlying siRNA-mediated gene silencing and efficacy; and the current clinical landscape and safety of approved siRNA therapeutics for immunotherapy. We examine the growing role of computationally guided design strategies and emerging machine-learning-based methods in optimizing siRNA chemical design, and outline how recent advances in siRNA chemical modification are expected to improve targeted gene modulation in the clinic. Additionally, we examine the role of delivery systems in enhancing siRNA potency, with an emphasis on tumor-targeted and tissue-specific approaches, as well as emerging combination therapies integrating siRNA with chemotherapy, immune checkpoint blockade, siRNA and mRNA co-delivery, and prodrug activation.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1897-1920"},"PeriodicalIF":3.9,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148723052","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

Activation of secondary metabolism in Aspergillus and related filamentous fungi through regulatory engineering. 通过调控工程激活曲霉及相关丝状真菌的次生代谢。

IF 3.9

RSC Chemical Biology Pub Date : 2026-08-07 eCollection Date: 2026-09-02 DOI: 10.1039/d6cb00043f

Jennifer Shyong, Clay C C Wang

{"title":"Activation of secondary metabolism in Aspergillus and related filamentous fungi through regulatory engineering.","authors":"Jennifer Shyong, Clay C C Wang","doi":"10.1039/d6cb00043f","DOIUrl":"10.1039/d6cb00043f","url":null,"abstract":"Filamentous fungi are major contributors to diverse secondary metabolites with broad applications to medicine, agriculture, and biotechnology. Advances in genome sequencing and bioinformatic tools have revealed that fungal genomes encode far more biosynthetic gene clusters (BGCs) than are expressed under normal laboratory conditions, leaving much biosynthetic potential transcriptionally silent. Overcoming this gap between predicted and observed secondary metabolism has become a major challenge in fungal natural product discovery. In this review, we summarize current strategies for activating silent or weakly expressed fungal BGCs through regulatory engineering, with an emphasis on approaches validated in Aspergillus, Penicillium, Monascus, and related filamentous fungi. We focus on genetic and chemical manipulations that enable coordinated activation of multiple biosynthetic pathways through chromatin-level modifiers, global transcriptional regulators, and developmental regulators. By framing these regulators as practical tools rather than solely biological components, we demonstrate their strengths, limitations, and applications in Aspergillus and related filamentous fungi. We further discuss emerging combinatorial and integrative approaches that use regulatory engineering alongside omics technologies and predictive tools, outlining alternatives and future directions for improving the interpretability of silent pathway activation.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1669-1686"},"PeriodicalIF":3.9,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148765870","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

Discovery of low molecular weight protein-binding fragments from bead-displayed libraries: application to monomeric proteins. 从头部显示文库中发现低分子量蛋白质结合片段：在单体蛋白质中的应用。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-28 eCollection Date: 2026-09-02 DOI: 10.1039/d6cb00128a

Joel Tong, Isuru M Jayalath, James V Parsons, Ju-An Kim, Matthew D Mann, Michal Tokmina-Roszyk, Thomas Kodadek

{"title":"Discovery of low molecular weight protein-binding fragments from bead-displayed libraries: application to monomeric proteins.","authors":"Joel Tong, Isuru M Jayalath, James V Parsons, Ju-An Kim, Matthew D Mann, Michal Tokmina-Roszyk, Thomas Kodadek","doi":"10.1039/d6cb00128a","DOIUrl":"10.1039/d6cb00128a","url":null,"abstract":"Fragment-based drug discovery (FBDD) is a powerful workflow for the development of drug candidates and probe molecules that begins with the discovery of one or more low affinity, low molecular weight ligands for a protein of interest (POI). Recently, we developed a simple fragment discovery platform in which TentaGel beads displaying many copies of the fragment are incubated with a fluorescently labeled multimeric protein. Association of two or more bead-displayed ligands with the multimeric target stabilizes the complex sufficiently to allow its detection even after rigorous washing. However, this simple \"pull-down\" assay cannot be used for monomeric protein targets since these complexes are too kinetically labile to survive being taken out of equilibrium. Here we explore various strategies to multimerize monomeric targets, thus allowing them to be used as targets in this fragment discovery platform. We find that a particularly effective and convenient strategy is to express a fusion of the POI with FOLDON, a 30-residue, homo-trimeric peptide.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1828-1838"},"PeriodicalIF":3.9,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148680349","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

Participation of redox-active residues in polysaccharide monooxygenase catalysis. 多糖单加氧酶催化中氧化还原活性残基的参与。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-27 eCollection Date: 2026-10-08 DOI: 10.1039/d6cb00144k

Allison E Batka, Aneesh Bhat, Alexander J Rose, Michael A Marletta

{"title":"Participation of redox-active residues in polysaccharide monooxygenase catalysis.","authors":"Allison E Batka, Aneesh Bhat, Alexander J Rose, Michael A Marletta","doi":"10.1039/d6cb00144k","DOIUrl":"10.1039/d6cb00144k","url":null,"abstract":"Polysaccharide monooxygenases (PMOs) degrade carbohydrate polymers via an oxidative mechanism involving activation of O2 or H2O2 at a mononuclear copper active site. The reaction with O2 requires the timely delivery of two electrons to the copper during each catalytic cycle. Large polymeric substrates might occlude the active site from reductant access, which raises questions of whether the substrate stays associated with the PMO during catalysis and whether there is an alternate path for electrons to reach the active site. Previous work provided evidence for electron transfer through residues Y168 (the axial tyrosine) and Y62 in an AA9 PMO, MtPMO9E. Results reported here further investigate these redox-active residues by comparing the Y62F/Y168F double variant (2F) to the wild-type (WT) enzyme. Oxidase activity and oxygenase activity were compared using three different reductants: cysteine, ascorbate, and cellobiose dehydrogenase. Unlike cysteine and ascorbate, cellobiose dehydrogenase is comparatively large and thought to be the native electron donor to fungal PMOs. The oxidase and oxygenase activities of 2F are significantly decreased compared to WT, but the peroxygenase activity is unaffected. The slow oxygenase activity of 2F suggests the PMO is preferentially reduced via the redox-active residues, although some reduction may occur directly at the active site when the substrate is present. Engineering tyrosine residues into an AA9 PMO that natively lacks the redox-active residues increases oxidase activity. The oxygenase reaction is first-order in the reductant, suggesting the rate-limiting step involves electron transfer between the reductant and the redox-active residues. These observations underscore the importance of redox-active residues in O2 utilization by PMOs.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"2069-2079"},"PeriodicalIF":3.9,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13462859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148722223","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

Non-specific cysteine modifications on proteins induced by trans-cyclooctene. 反式环烯诱导蛋白质的非特异性半胱氨酸修饰。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-27 eCollection Date: 2026-09-02 DOI: 10.1039/d6cb00166a

Zhijian Yan, Wei Qin

引用次数: 0

Proteome-wide target profiling of α-helix mimetics. α-螺旋模拟物的蛋白质组范围靶标分析。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-21 eCollection Date: 2026-09-02 DOI: 10.1039/d6cb00065g

Amrita Date, Archie Wall, Hannah Kiely-Collins, Theo Flack, Jack W Houghton, Jianan Lu, Adam M Thomas, Peiyu Zhang, Andrew J Wilson, Edward W Tate, Anna Barnard

引用次数: 0

Ant abaecin-2 is a context-dependent copper-binding effector that can be either inhibitory or protective. 蚂蚁abaecin-2是一种环境依赖的铜结合效应，可以抑制或保护。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-20 eCollection Date: 2026-09-02 DOI: 10.1039/d6cb00146g

Caroline M Donaghy, Helena V Heyer-Gray, Charlotte O'Hern, Michael Ibrahim, Bryant Perez-Torres, Nichali Bogues, Andrei T Alexandrescu, Karrera Y Djoko, Jonathan L Klassen, Alfredo M Angeles-Boza

{"title":"Ant abaecin-2 is a context-dependent copper-binding effector that can be either inhibitory or protective.","authors":"Caroline M Donaghy, Helena V Heyer-Gray, Charlotte O'Hern, Michael Ibrahim, Bryant Perez-Torres, Nichali Bogues, Andrei T Alexandrescu, Karrera Y Djoko, Jonathan L Klassen, Alfredo M Angeles-Boza","doi":"10.1039/d6cb00146g","DOIUrl":"10.1039/d6cb00146g","url":null,"abstract":"Host defense peptides (HDPs) are important components of the innate immune system that are used to combat pathogens and often rely on binding trace nutrient metals for their function. However, controlling nutrient metals may have other roles in host-symbiont interactions beyond poisoning harmful pathogens. This study characterizes the evolution, structural properties, and biochemical activity of the novel hymenopteran HDP abaecin-2. In myrmicine ants such as the fungus-growing tribe Attini, abaecin-2 has evolved to include an Amino-Terminal Cu(ii) and Ni(ii)-binding (ATCUN) motif, which we hypothesize binds copper, a trace nutrient that is enriched in attine ant colonies. Combined results from mass spectrometry, competitive binding assays, circular dichroism, and NMR indicate that the abaecin-2 peptide lacks a defined secondary structure and can associate with up to 2 Cu(ii) ions, one strongly bound at the ATCUN motif and another weakly bound, likely at a conserved histidine residue. Despite its copper-binding activity, abaecin-2 alone does not exhibit antibacterial activity against Escherichia coli or Bacillus subtilis (models for bacteria that live in ant fungus gardens). However, it synergizes with a model pore-forming peptide cecropin A to inhibit the growth of E. coli, similar to the related peptide abaecin-1. The copper-binding activity conferred by the ATCUN motif also protects copper-sensitive E. coli from excess copper toxicity. The dual context-dependent inhibitory and protective roles for abaecin-2 indicate that this previously under-characterized HDP may be used by attine ants to regulate both harmful and beneficial symbionts.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1804-1817"},"PeriodicalIF":3.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148585502","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