RSC Chemical Biology最新文献

{"title":"Achieving cell-type selectivity in metabolic oligosaccharide engineering","authors":"Michelle Marie B. Helmeke, Rhianna L. Haynie-Cion and Matthew R. Pratt","doi":"10.1039/D5CB00168D","DOIUrl":"10.1039/D5CB00168D","url":null,"abstract":"<p >Metabolic oligosaccharide engineering (MOE) is a transformative technology, enabling the chemical labeling and subsequent analysis of glycans. Central to this method are monosaccharide analogs, termed metabolic chemical reporters (MCRs), that contain abiotic functional groups that can undergo an increasing number of bioorthogonal reactions. Typically, these abiotic groups were designed to be as small as possible, allowing them to be tolerated by metabolic enzymes and glycosyltransferases that transform MCRs into donor sugars and add them into glycans, respectively. This generality allows MCRs to be used by a variety of cells and tissues but can also be a limitation in their application to investigate glycosylation of specific cell-types in multicellular systems. Here, we review different methods that are beginning to transition MCRs into cell selective tools, with the potential to increase the already large impact these compounds have had on glycoscience.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 10","pages":" 1506-1520"},"PeriodicalIF":3.1,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12364120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144972905","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":"Investigating the N-terminal linker histone H1 subtypes as substrates for JmjC lysine demethylases","authors":"Vildan A. Türkmen, Anthony Tumber, Eidarus Salah, Samanpreet Kaur, Christopher J. Schofield and Jasmin Mecinović","doi":"10.1039/D5CB00083A","DOIUrl":"10.1039/D5CB00083A","url":null,"abstract":"<p >Members of the Jumonji C (JmjC) subfamily of non-heme Fe(<small>II</small>) and 2-oxoglutarate (2OG) dependent <em>N</em><small>^ε</small>-lysine demethylases have established roles in catalysing demethylation of <em>N</em><small>^ε</small>-methylated lysine residues in core histones; their roles in accepting linker H1 histones as substrates have been less well explored. We report studies on the H1 substrate specificity of human JmjC lysine demethylases (KDMs), specifically KDM3A-C, KDM4A, KDM4D, KDM4E, KDM5D, and KDM6B, for mono-, di- and trimethylated <em>N</em><small>^ε</small>-lysine residues in peptide fragments of the N-terminal tail of human linker histone H1 isoforms (H1.2, H1.3, H1.4 and H1.5). The KDM4s, but not the other tested JmjC KDMs, catalysed demethylation of tri- and dimethylated H1 peptide isoforms with activities: KDM4E &gt; KDM4D &gt; KDM4A. The order of substrate preference for KDM4E was H1.2K26me3 &gt; H1.5K26me3 ≈ H1.3K24me3 &gt; H1.2K25me3 ≈ H1.4K25me3. For KDM4D, the most efficient tested substrate was H1.5K26me3. Among the dimethylated H1 peptide isoforms, H1.3K24me2 appeared to be the most efficient KDM4E substrate, with comparable activity to the core histone H3K9me2 substrate. The results demonstrate that JmjC KDM4s can accept the N-terminal H1 tails as substrates, further highlighting the potential for flexibility in substrate and product selectivity of the JmjC KDMs, in particular, within the KDM4 subfamily. Molecular and cellular investigations on JmjC KDM-catalysed H1 demethylation are of molecular and biomedical interest.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 10","pages":" 1607-1615"},"PeriodicalIF":3.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144972989","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":"Applications of click and click-to-release chemistry in biomaterials to advance skin regeneration","authors":"Merel Gansevoort, Matthijs van de Waarsenburg, Thomas J. Boltje, Floris P. J. T. Rutjes, Toin H. van Kuppevelt and Willeke F. Daamen","doi":"10.1039/D5CB00065C","DOIUrl":"10.1039/D5CB00065C","url":null,"abstract":"<p >Achieving skin regeneration following destruction of the epidermis and dermis (<em>e.g.</em> full-thickness wounds) has remained an unachieved goal. The wound healing response is complex and consists of multiple overlapping phases which are tightly choreographed by the ebb and flow of effector molecules. Mimicking this spatiotemporal aspect in pro-regenerative biomaterials may enhance their efficacy and eventually lead to skin regeneration. However, robust spatiotemporal signalling has remained difficult to achieve. The field of bioorthogonal click and click-to-release chemistry may be key to creating spatiotemporal signalling biomaterials. The ability to safely and effectively conjugate or release molecules in complex biological environments has transformed many areas of research. In this review, we aim to highlight the complex nature of wound healing and address how click and click-to-release chemistry approaches could contribute to the development of biomaterials with spatiotemporal control over effector molecules.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 10","pages":" 1521-1531"},"PeriodicalIF":3.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144972862","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":"P450 cyptide synthase MpoB catalyzes the cross-linking of the YPW motif on the precursor peptide†","authors":"Abujunaid Habib Khan, Jabal Rahmat Haedar, Vic Kiselov, Viktors Romanuks, Gints Smits, Stefano Donadio and Chin-Soon Phan","doi":"10.1039/D5CB00153F","DOIUrl":"10.1039/D5CB00153F","url":null,"abstract":"<p >Cytochrome P450 enzymes in ribosomally synthesized and post-translationally modified peptides (RiPPs) catalyze C–C, C–N, or C–O cross-linking reactions in the biosynthesis of biaryl cyclophane natural products. Here, we manually identified 127 homologous P450s linked to putative precursor peptides containing the YPW motif. Through <em>in vivo</em> functional studies in <em>Escherichia coli</em>, the newly identified enzyme MpoB from <em>Micromonospora polyrhachis</em> DSM 45886 was found to catalyze the formation of a cross-link between Tyr-C3 and Trp-N1 at the YPW motif. This result provides an additional toolkit for cross-linked peptide modification.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 9","pages":" 1386-1390"},"PeriodicalIF":3.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733731","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":"Semi-enzymatic synthesis and application of 13C-isotopically labelled inositol-(1,4,5)-trisphosphate†","authors":"Atharva Patharkar, Meike Amma, Jaime Isern, Zoé Chaudron, Angélique Besson-Bard, Valérie Nicolas-Francès, Claire Rosnoblet, David Wendehenne, Peter Schmieder and Dorothea Fiedler","doi":"10.1039/D5CB00139K","DOIUrl":"10.1039/D5CB00139K","url":null,"abstract":"<p >Inositol-(1,4,5)-trisphosphate (Ins(1,4,5)P<small>₃</small>) is a crucial secondary messenger that controls calcium (Ca<small>²⁺</small>) levels inside cells, yet many questions regarding Ins(1,4,5)P<small>₃</small> metabolism are challenging to address with current methods. Here, a semi-enzymatic milligram scale synthesis of isotopically labeled [<small>¹³</small>C<small>₆</small>]Ins(1,4,5)P<small>₃</small> is reported which then served as a substrate to monitor the activity of mammalian type II inositol 1,4,5-trisphosphate 5-phosphatase INPP5B, using NMR spectroscopy in real time. In addition, the phosphorylation sequence catalyzed by inositol polyphosphate multikinase IPMK was confirmed using [<small>¹³</small>C<small>₆</small>]Ins(1,4,5)P<small>₃</small> and 2D NMR spectroscopy. The method was subsequently applied to characterize the phosphorylation/dephosphorylation reactions of a putative inositol phosphate kinase from the alga <em>Klebsormidium nitens</em> (<em>Kn</em>IPK2). <em>Kn</em>IPK2 displayed 6-kinase activity towards [<small>¹³</small>C<small>₆</small>]Ins(1,4,5)P<small>₃</small>, and dual 4/6- and 5-phosphatase activity towards [<small>¹³</small>C<small>₆</small>]Ins(1,3,4,5,6)P<small>₅</small>. Finally, [<small>¹³</small>C<small>₆</small>]Ins(1,4,5)P<small>₃</small> was utilized as an internal standard in hydrophilic liquid interaction chromatography mass spectrometry (HILIC-MS) experiments, to quantify dephosphorylation of Ins(1,4,5)P<small>₃</small> by INPP5B. [<small>¹³</small>C<small>₆</small>]Ins(1,4,5)P<small>₃</small> therefore constitutes a broadly applicable analytical tool that should facilitate the characterization of Ins(1,4,5)P<small>₃</small> metabolism in the future.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 9","pages":" 1426-1436"},"PeriodicalIF":3.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12301848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144745397","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":"Defining STING–sterol interactions with chemoproteomics†","authors":"Ian Ford, Miranda Villanueva, Min Sub Lee, Quan D. Zhou, Constance Yuen, Robert Damoiseaux, Steven J. Bensinger and Keriann M. Backus","doi":"10.1039/D5CB00171D","DOIUrl":"10.1039/D5CB00171D","url":null,"abstract":"<p >Stimulator of interferon genes (STING) is an intracellular pattern recognition receptor that plays a key role in responding to cytosolic DNA and cyclic dinucleotides. STING activity is tightly regulated to avoid aberrant STING activity, excessive type I IFN responses, and resultant autoinflammatory disease. As such understanding the molecular events regulating STING activity is critical. Recent work has revealed cellular cholesterol metabolism also functions to modulate STING activity, although the molecular events linking cholesterol homeostasis with STING remain incompletely understood. Here we pair genetic and chemoproteomic approaches to inform the mechanisms governing cholesterol modulation of STING activity. Using gain- and loss-of-function systems, we find that markedly increasing SCAP-SREBP2 processing and resultant cholesterol synthesis has little impact on STING activity. In contrast, we find that genetic deletion of <em>Srebf2</em> increased basal and ligand inducible type I IFN responses. Thus, STING can function in the absence of the SCAP-SREBP2 protein apparatus. Through activity-based protein profiling with three distinct sterol-mimetic probes, we provide direct evidence for STING–sterol binding. We also find that the mitochondrial protein VDAC1 co-purifies with STING and binds to sterol-mimetic probes. We also show that STING's subcellular localization is responsive to modulation of cellular sterol content. Our findings support a model where sterol synthesis in the ER regulates STING activity, aligning with recent studies indicating that cholesterol-mediated retention of STING in the endoplasmic reticulum occurs through cholesterol recognition amino acid consensus (CARC) motifs in STING.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 9","pages":" 1451-1464"},"PeriodicalIF":3.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12308517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144761718","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":"Photoactivatable and photolabile pharmacophores: lessons learned from capsaicin†","authors":"Nils Imse, Lucia Rojas, Cristina Gil Herrero, Sebastian Thallmair, JeongSeop Rhee and Nadja A. Simeth","doi":"10.1039/D5CB00124B","DOIUrl":"10.1039/D5CB00124B","url":null,"abstract":"<p >Light-controlled molecules have become valuable tools for studying biological systems offering an unparalleled control in space and time. Specifically, the remote-controllable (de)activation of small molecules is attractive both to study molecular processes from a fundamental point of view and to develop future precision therapeutics. While pronounced changes through light-induced cleavage of photolabile protecting groups and the accompanying liberation of bioactive small molecules have become a highly successful strategy, approaches that focus solely on the revert process, <em>i.e.</em> the photochemical deactivation of bioactive agents, are sparse. In this work, we studied whether a given bioactive compound could be made photolability by structural design. We thus used the example of capsaicinoids, which control the transient receptor potential cation channel subfamily V member 1 (TRPV1), to generate both suitable light activation and deactivation strategies.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 9","pages":" 1473-1482"},"PeriodicalIF":3.1,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776460","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":"Synergy of triazolyl substituents at C1 and C3 of galactose for high-affinity and selective galectin-4C inhibition†","authors":"Alexander Dahlqvist, Rob Marc Go, Chandan Kishor, Hakon Leffler, Helen Blanchard and Ulf J. Nilsson","doi":"10.1039/D5CB00106D","DOIUrl":"10.1039/D5CB00106D","url":null,"abstract":"<p >Galectins are a family of carbohydrate-recognising proteins involved in regulation of cell adhesion and cell signaling, leading to roles in <em>e.g.</em> cancer progression, fibrosis, and ulcerative colitis. Glycomimetic galectin inhibitors based on different molecular scaffolds are known and have demonstrated effects from cell experiments to the clinic. Presented here is the synthesis and evaluation of 3-aryltriazolyl-C1-galactosyls leading to discovery of an unexpected synergy effect between C1 and C3 triazolyl substituents to give galectin-4C (C-terminal domain) inhibitors with affinities down to 9.5 μM and up to thirty-sevenfold selectivity for galectin-4C over other galectins. X-ray structural analysis of one inhibitor:galectin-4C complex revealed that both the C1 and C3 arene-substituents engage in interactions with the galectin-4C binding site. These molecules have potential as lead compounds towards discovery of galectin-4-targeting compounds addressing inflammatory conditions, such as inflammatory bowel disease and ulcerative colitis.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 9","pages":" 1437-1450"},"PeriodicalIF":3.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144745398","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":"Regioselective rapid ene-type reaction (RRER) enables bioconjugation of histone serotonylation†","authors":"Jinghua Wu, Huapeng Li, Adam R. Lovato, Andrew Symasek, Zeng Lin and Qingfei Zheng","doi":"10.1039/D5CB00159E","DOIUrl":"10.1039/D5CB00159E","url":null,"abstract":"<p >Triazolinedione (TAD) derivatives have been commonly utilized as protection and labeling reagents for indole and phenol moieties <em>via</em> a reversible ene-type reaction. Previous studies showed that the TAD probes could selectively modify tyrosine and tryptophan side-chains within proteins and peptides under distinct pH conditions. Here, we report a pH-controlled regioselective rapid ene-type reaction (RRER) between TAD and 5-hydroxyindole, where the modification occurs on the C4 position rather than the C3 of inactivated indole rings. Employing this unique reaction, we have performed the selective bioconjugation of serotonylation occurring on the fifth amino acid residue, glutamine, of histone H3 (H3Q5), which does not contain any tryptophan in its protein sequence. Finally, RRER was applied to determine the H3Q5 serotonylation levels in cultured cells and tissue samples, which served as a newly developed powerful tool for <em>in vitro</em> and <em>in vivo</em> histone monoaminylation analysis. Overall, our findings in this research expanded the chemical biology toolbox for investigating histone monoaminylation and facilitated the understandings of TAD-mediated ene-type reactions.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 8","pages":" 1278-1283"},"PeriodicalIF":3.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699844","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":"Discovery of an exquisitely selective WDR5 chemical probe accelerated by a high-quality DEL–ML Hit†","authors":"Lasse Hoffmann, Christopher Lenz, Frederic Farges, Serah W. Kimani, Johannes Dopfer, Sabrina Keller, Martin Peter Schwalm, Hanna Holzmann, Andreas Kraemer, Aiping Dong, Fengling Li, Irene Chau, Levon Halabelian, Matthias Gstaiger, Susanne Müller, Stefan Knapp and Václav Němec","doi":"10.1039/D5CB00109A","DOIUrl":"10.1039/D5CB00109A","url":null,"abstract":"<p >Herein we present the rapid development of LH168, a potent and highly selective chemical probe for WDR5, streamlined by utilizing a DEL–ML (DNA encoded library–machine learning) hit as the chemical starting point. LH168 was comprehensively characterized in bioassays and demonstrated potent <em>in cellulo</em> target engagement at the WIN-site pocket of WDR5, with an EC<small>₅₀</small> of approximately 10 nM, a long residence time, and exceptional proteome-wide selectivity for WDR5. In addition, we present the X-ray co-crystal structure and provide insights into the structure–activity relationships (SAR). In parallel, we developed a matched negative control compound as well as an alkyne analog (compound <strong>16</strong>) to facilitate the development of bifunctional molecules. Taken together, we provide the scientific community with a well-characterized chemical probe to enable studies and functional manipulation of WDR5 in a cellular context, as this protein represents a therapeutically relevant target with scaffolding functions that influence multiple cellular processes.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 10","pages":" 1585-1594"},"PeriodicalIF":3.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12415533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030748","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}