RSC Chemical Biology最新文献

Correction: Dynamic conformational equilibria in the active states of KRAS and NRAS. 更正：KRAS和NRAS活性态的动态构象平衡。

IF 3.1

RSC Chemical Biology Pub Date : 2026-05-05 DOI: 10.1039/d6cb90018f

Enrico Rennella, Chrystèle Henry, Callum J Dickson, Florian Georgescauld, Thomas E Wales, Dirk Erdmann, Simona Cotesta, Michel Maira, Richard Sedrani, Saskia M Brachmann, Nils Ostermann, John R Engen, Lewis E Kay, Kim S Beyer, Rainer Wilcken, Wolfgang Jahnke

引用次数: 0

A new 4-atom linker enables PROTAC development and imaging. 新的4原子连接器使PROTAC的开发和成像成为可能。

IF 3.1

RSC Chemical Biology Pub Date : 2026-04-30 DOI: 10.1039/d6cb00127k

Spyros Letsios, Giovana Carrasco, Martin Lee, Mateen Wagiet, Marta Madureira, Marley Samways, Zaid Khan, Valerie G Brunton, Olivera Grubisha, Alison N Hulme

{"title":"A new 4-atom linker enables PROTAC development and imaging.","authors":"Spyros Letsios, Giovana Carrasco, Martin Lee, Mateen Wagiet, Marta Madureira, Marley Samways, Zaid Khan, Valerie G Brunton, Olivera Grubisha, Alison N Hulme","doi":"10.1039/d6cb00127k","DOIUrl":"https://doi.org/10.1039/d6cb00127k","url":null,"abstract":"Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional molecules, emerging as a promising class of drugs. Amongst their structural components, the linker moiety plays a pivotal role in modulating their biological activity and physicochemical properties. Current PROTAC design strategies involve utilising shorter and more rigid linkers to limit the number of possible conformations within the ternary complex. We hypothesised that employing a short diyne spacer as the linker between the two ligands could generate highly potent PROTACs. Here, we report a series of diyne-bearing, low nanomolar BRD4 degraders recruiting the CRL4CRBN E3 ligase complex. As well as providing highly-active degraders, the Raman-active diyne moiety also enables the label-free visualisation of intracellular drug uptake at low micromolar concentrations via stimulated Raman scattering (SRS) microscopy. This work demonstrates the potential of diyne-based PROTAC linkers for both drug development and to address a key challenge within the field in understanding the cellular uptake mechanisms and intracellular localisation of PROTACs.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13141859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147844353","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

Prochelators modulate azole activity against Candida albicans in a metal-dependent manner. 促螯剂以金属依赖的方式调节抗白色念珠菌的唑活性。

IF 3.1

RSC Chemical Biology Pub Date : 2026-04-29 DOI: 10.1039/d6cb00073h

Madeline Ann Merriman, Catherine A Denning-Jannace, Andrea Barboza Hurtado, Francesca A Vaccaro, Yu-Shien Sung, Elisa Tomat, Katherine J Franz

引用次数: 0

A fluorescence-activated droplet sorting assay for ultra-high-throughput screening of PET hydrolases based on a pH indicator. 基于pH指示剂的PET水解酶超高通量筛选荧光激活液滴分选试验。

IF 3.1

RSC Chemical Biology Pub Date : 2026-04-29 DOI: 10.1039/d6cb00122j

Maxine Yew, Haizhen Bi, Dingjie Wang, Rui Qi, Huiling Yuan, Huanhuan Zhai, Gen Li, Qinhong Wang, Leilei Zhu

{"title":"A fluorescence-activated droplet sorting assay for ultra-high-throughput screening of PET hydrolases based on a pH indicator.","authors":"Maxine Yew, Haizhen Bi, Dingjie Wang, Rui Qi, Huiling Yuan, Huanhuan Zhai, Gen Li, Qinhong Wang, Leilei Zhu","doi":"10.1039/d6cb00122j","DOIUrl":"https://doi.org/10.1039/d6cb00122j","url":null,"abstract":"The continuous discovery and engineering of polyethylene terephthalate (PET) hydrolases are critical to advancing sustainable plastic recycling. A significant number of PET hydrolases have been identified to date; nonetheless, high-throughput screening and evaluation of enzyme characteristics remain a key bottleneck in protein engineering. This study develops an ultra-high-throughput fluorescence-activated droplet sorting (FADS) system for screening PET hydrolases, based on pH sensing. The pH change caused by the released depolymerization product, terephthalic acid (TPA), is correlated with the fluorescent variation of the pH-sensitive C-SNARF-4F probe. We applied this method to screen mutant libraries of two PET hydrolases, DepoPETase β and a new enzyme, SdPETase (derived from Saccharopolyspora dendranthemae), identified via genome mining. Variants exhibiting 1.21-fold and 2.65-fold higher hydrolytic activities were successfully obtained for DepoPETase β and SdPETase, respectively. The successful integration of the pH-based assay with FADS highlights its versatility and efficiency for ultra-high-throughput screening of PET hydrolases.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13126315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821847","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

Mixed squaramide thioesters as phosphate group analogues for non-competitive antagonists of the phospholipid-sensing G protein-coupled receptor GPR55. 混合角酰胺硫酯作为磷脂敏感G蛋白偶联受体GPR55非竞争性拮抗剂的磷酸基类似物。

IF 3.1

RSC Chemical Biology Pub Date : 2026-04-24 DOI: 10.1039/d5cb00231a

Junpei Abe, Xianyue Huang, Nozomi Ishii, Itaru Imayoshi, Yoshio Hirabayashi, Ichiro Matsuo, Hiroyuki Kamiguchi, Yukishige Ito, Adam T Guy, Peter Greimel

{"title":"Mixed squaramide thioesters as phosphate group analogues for non-competitive antagonists of the phospholipid-sensing G protein-coupled receptor GPR55.","authors":"Junpei Abe, Xianyue Huang, Nozomi Ishii, Itaru Imayoshi, Yoshio Hirabayashi, Ichiro Matsuo, Hiroyuki Kamiguchi, Yukishige Ito, Adam T Guy, Peter Greimel","doi":"10.1039/d5cb00231a","DOIUrl":"https://doi.org/10.1039/d5cb00231a","url":null,"abstract":"High-affinity inhibitors of specific receptors are a valuable tool to elucidate cellular signaling, control biological systems and develop therapeutic drugs. Here, we report mixed squaramide thioesters as a novel electrophilic handle, demonstrating an optimal balance between nucleophile accessibility and hydrolytic stability in aqueous environments. Density function theory calculations show that the energy of the lowest unoccupied molecular orbital (LUMO) of mixed squaramide thioesters is lower compared to mixed squaramide esters, rendering them more reactive to nucleophilic attack. Synthetic access to various lysophosphatidylglucoside (LysoPtdGlc) analogues incorporating mixed squaramide thioesters as phosphate bioisosteres was readily established by condensation of mixed squaramide esters with the corresponding thiols. Next, we characterised the inhibitory activity of these analogues in biological assays of axon growth cone chemotropism in cultured primary nociceptive neurons. These synthetic analogues induce both acute and sustained (more than 12 h) inhibition of the GPR55/LysoPtdGlc signaling. This inhibition resulted in sustained antagonistic attenuation of GPR55-mediated axon chemotropism while preserving growth cone sensitivity to other GPR55-independent chemotropic signaling molecules. Our findings demonstrate the potential of thiosquaramide-based phosphate bioisosteres as highly specific inhibitors with well controlled reactivity, expanding the repertoire of modulators for lipid-sensing GPCRs.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13107339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147784713","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

Igalan attenuates sepsis-induced inflammation through covalent targeting of the NLRP3 inflammasome pathway. Igalan通过共价靶向NLRP3炎症小体途径减轻败血症诱导的炎症。

IF 3.1

RSC Chemical Biology Pub Date : 2026-04-23 DOI: 10.1039/d5cb00280j

Chengchen Hou, Yang Chen, Wenjie Bi, Lin Gao, Simiao Yu, Xiaowen Zhang, Zekun Chen, Tiantian Wei, Dilnoza E Dusmatova, Rimma F Mukhamatkhanova, Ildar D Sham'yanov, Liwen Han, Zhiyuan Lu, Hua Wang, Nilufar Z Mamadalieva, Kewu Zeng

{"title":"Igalan attenuates sepsis-induced inflammation through covalent targeting of the NLRP3 inflammasome pathway.","authors":"Chengchen Hou, Yang Chen, Wenjie Bi, Lin Gao, Simiao Yu, Xiaowen Zhang, Zekun Chen, Tiantian Wei, Dilnoza E Dusmatova, Rimma F Mukhamatkhanova, Ildar D Sham'yanov, Liwen Han, Zhiyuan Lu, Hua Wang, Nilufar Z Mamadalieva, Kewu Zeng","doi":"10.1039/d5cb00280j","DOIUrl":"https://doi.org/10.1039/d5cb00280j","url":null,"abstract":"Macrophages play a critical role in sepsis, a life-threatening systemic inflammatory syndrome that necessitates urgent therapeutic intervention. Unfortunately, no approved drugs currently target this specific pathological mechanism. In this study, we identify Igalan, a natural compound that selectively disrupts macrophage-mediated inflammatory cascades in macrophages. Mechanistic studies demonstrate that Igalan alleviates oxidative stress and maintains mitochondrial integrity. Crucially, we reveal that Igalan covalently modifies the NLRP3 (NLR family pyrin domain containing 3) NACHT domain, thereby irreversibly suppressing inflammasome activation and subsequent pro-inflammatory signaling. In vivo studies demonstrate potent therapeutic effects of Igalan, mitigating systemic inflammation in LPS-challenged zebrafish and providing protection against pulmonary injury and intestinal barrier dysfunction in murine sepsis models. Collectively, our work establishes Igalan as a covalent NLRP3 inhibitor with translational potential for sepsis treatment.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147844385","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

Decoding protein-phospholipid interaction networks in cancer: the role of acyl-chain remodeling. 解码癌症中蛋白质-磷脂相互作用网络：酰基链重塑的作用。

IF 3.1

RSC Chemical Biology Pub Date : 2026-04-23 DOI: 10.1039/d6cb00015k

Berit Blume, Grace Potter, Carsten Schultz, Andrew Emili

{"title":"Decoding protein-phospholipid interaction networks in cancer: the role of acyl-chain remodeling.","authors":"Berit Blume, Grace Potter, Carsten Schultz, Andrew Emili","doi":"10.1039/d6cb00015k","DOIUrl":"https://doi.org/10.1039/d6cb00015k","url":null,"abstract":"Lipids, particularly phosphoinositides, are increasingly recognized as important markers and causal regulators in cancer progression. Less appreciated, however, are the functional consequences of changes in phospholipid acyl chain length and saturation. These alterations reshape membrane biophysics and rewire membrane-associated signaling complexes, suggesting that acyl-chain remodeling represents an emerging regulatory layer in cancer biology. Distinct tumor types or their models exhibit characteristic acyl chain profiles, often shifting toward shorter, more saturated chains that alter physical and functional interactions. Stress conditions and the tumor microenvironment further diversify these profiles, linking acyl chain composition to cellular plasticity, invasiveness, and metastatic potential. In this review, we summarize the molecular factors and enzymatic pathways that govern phospholipid acyl chain remodeling in cancer and examine their relevance to dynamic protein interaction networks. We describe how dysregulated lipid metabolism at the fatty acid level intersects with oncogenic signaling and highlight emerging chemical biology and multi-omics approaches that enable interrogation of protein-phospholipid interaction networks in physiological contexts. Together, these developments position acyl chain-resolved lipid analysis as a central challenge in chemical biology, requiring new probe design and integrative data frameworks to decode lipid-protein interaction networks in cancer. Finally, we discuss how emerging tools for acyl chain-resolved lipid analysis and targeted modulation reveal how membrane remodeling rewires signaling pathways and reshapes the tumor lipid-protein interactome, opening new opportunities for cancer diagnosis and therapeutic intervention.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13140690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147844443","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

Backbone N-heteroatom substitution as a strategy to enhance peptide proteolytic stability. 主链n -杂原子取代作为提高肽蛋白水解稳定性的策略。

IF 3.1

RSC Chemical Biology Pub Date : 2026-04-23 DOI: 10.1039/d6cb00061d

Avraz F Anwar, Natalia Cano-Sampaio, Juan R Del Valle

{"title":"Backbone N-heteroatom substitution as a strategy to enhance peptide proteolytic stability.","authors":"Avraz F Anwar, Natalia Cano-Sampaio, Juan R Del Valle","doi":"10.1039/d6cb00061d","DOIUrl":"https://doi.org/10.1039/d6cb00061d","url":null,"abstract":"Peptide-based ligands are well-suited to engage large biomolecular surfaces but are often limited by rapid proteolytic degradation in biological environments. Backbone modification offers a direct means to disrupt protease recognition while preserving side chain functionality; however, many established approaches impose conformational constraints that compromise biological activity. Here, we evaluate backbone N-amino and N-hydroxy substitution as a strategy for enhancing peptide proteolytic stability. Using a defined chymotrypsin substrate, we demonstrate that backbone N-amination confers pronounced, position-dependent protection when introduced at or adjacent to the scissile bond. Extending these findings to a β-sheet-forming antimicrobial peptide, we show that poly-N-amination dramatically enhances serum stability while preserving or enhancing conformation-dependent antibacterial activity. Together, these results expand the repertoire of peptide backbone modifications that mitigate proteolytic degradation while retaining the conformational and functional features required for the design of peptide- and protein-based biological probes.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147844425","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

Methylene insertion reveals the importance of phosphate-phosphate distance in DNase I cleavage. 亚甲基插入揭示了磷酸-磷酸距离在dna酶I切割中的重要性。

IF 3.1

RSC Chemical Biology Pub Date : 2026-04-21 DOI: 10.1039/d6cb00024j

Ayano Nagaya, Kohji Seio, Yoshiaki Masaki

引用次数: 0

Enhancing mRNA stability and translational potential through tailored modifications at the 3' end. 通过在3'端定制修饰增强mRNA的稳定性和翻译潜力。

IF 3.1

RSC Chemical Biology Pub Date : 2026-04-17 DOI: 10.1039/d6cb00033a

Olga Perzanowska, Joanna Kowalska, Jacek Jemielity

{"title":"Enhancing mRNA stability and translational potential through tailored modifications at the 3' end.","authors":"Olga Perzanowska, Joanna Kowalska, Jacek Jemielity","doi":"10.1039/d6cb00033a","DOIUrl":"https://doi.org/10.1039/d6cb00033a","url":null,"abstract":"Poly(A) tails regulate mRNA turnover and translation through multiple RNA-protein interactions, and deadenylation is the initiating step of the major cytoplasmic decay pathways. Here, we report a simple post-transcriptional strategy to protect the 3' end of synthetic mRNA by enzymatically ligating short, chemically modified 5'-phosphorylated dinucleotides. Using T4 RNA ligase 1, we attached 2'-O-methyl and/or phosphorothioate containing A- or G-dinucleotides to the 3' end of model oligoadenylates and to an IVT Gaussia luciferase (GLuc) mRNA bearing an ∼150-nt poly(A) tail. All ligated products showed strong resistance to human CNOT7-mediated deadenylation in vitro, whereas the unmodified control mRNA underwent poly(A) removal. In rabbit reticulocyte lysate, 3'-modified GLuc mRNAs translated comparably to the control, indicating minimal interference with the translational machinery. In mammalian cells (A549, JAWSII and HEK293), the protein output depended on the dinucleotide structure and cell type; two adenosine donors-pApAm and the D1 phosphorothioate stereoisomer pApsAm-consistently performed best, increasing the cumulative GLuc production up to 163% in HEK293 and up to 79% in A549. These results establish dinucleotide ligation as a minimal and modular 3'-end engineering approach that enhances resistance to deadenylation and can improve the translational performance of therapeutic mRNA candidates.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821906","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