RSC Chemical Biology最新文献

{"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}

{"title":"Chemoenzymatic synthesis of sialylated and fucosylated mucin analogs reveals glycan-dependent effects on protein conformation and degradation†","authors":"Amanda M. Wood, Casia L. Wardzala and Jessica R. Kramer","doi":"10.1039/D5CB00111K","DOIUrl":"10.1039/D5CB00111K","url":null,"abstract":"<p >Mucin proteins are essential for life but are challenging to study due to their complex glycosylation patterns. Synthetic mimics have become vital tools for understanding and modulating the roles of mucins in human health and disease. These materials also have diverse biomedical applications as lubricants and anti-infectives, in vaccine formulations, and more. We developed a chemoenzymatic approach to prepare polypeptide-based synthetic mucins displaying a variety of glycans with native linkages and orientations. By combining the polymerization of glycosylated amino acid <em>N</em>-carboxyanhydrides with enzymatic sialylation and fucosylation, we produced a tunable panel of synthetic mucins. These polymers were recognized by natural glycan-binding and glycan-degrading enzymes, providing insights into the structural preferences of these proteins. Glycan- and linkage-dependent effects on proteolysis were observed. Further, investigation of the influence of glycans on peptide backbone secondary structure revealed that both sialylation and linkage at Ser <em>vs.</em> Thr have profound effects on hierarchical conformation. Overall, our methodology offers versatile tools for exploring the diverse glycobiology of mucins.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 8","pages":" 1336-1352"},"PeriodicalIF":3.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660696","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":"Random peptide mixtures of tryptophan and lysine suppress the aggregation of a cancer-related mutant of the Axin protein†","authors":"Tommaso Garfagnini, Zvi Hayouka and Assaf Friedler","doi":"10.1039/D5CB00141B","DOIUrl":"10.1039/D5CB00141B","url":null,"abstract":"<p >Aggregation of dysfunctional proteins can lead to a variety of diseases including cancer. We have previously developed chaperone-derived peptides that inhibit aggregation of the cancer-related L106R mutant of Axin RGS. Here we show that significantly improved inhibition was achieved using random peptide mixtures (RPMs) designed to mimic the chemical characteristics of the chaperone-like peptides. 20-mer RPMs of tryptophan and lysine suppressed aggregation of Axin RGS L106R with up to 50-fold improved activity compared to parent inhibitors. Conversely, peptides derived from the lead hotspot of Axin RGS aggregation that were designed to be specific, were unable to prevent aggregation of the protein. RPMs constitute the most efficient strategy to date to magnify peptide inhibitory activity against Axin RGS L106R aggregation, as they contain multiple active species and conformations that cover a larger inhibitory space and shield multiple hotspots at once. Our results demonstrate that the chemical composition of the peptide, and not the specific sequence, is the key factor for inhibitory activity.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 8","pages":" 1270-1277"},"PeriodicalIF":3.1,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660697","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}