ChemBioChem最新文献_第7页

Genome Mining Reveals a Novel Nephthenol-Producing Diterpene Synthase from the Sandfly Lutzomyia Longipalpis 基因组挖掘揭示了白蛉一种新的产肾酚二萜合成酶。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2025-07-09 DOI: 10.1002/cbic.202500292

Charles Ducker, Catherine McKeown, Igor F. P. Da Silva, Isis Torres Souza, John A. Pickett, Antônio E. G. Santana, Neil J. Oldham

引用次数: 0

Docking and Molecular Dynamics Simulation-Based Analysis of Advanced Small-Molecule Kinase Inhibitors Identified pre-let-7 miRNA Binders. 基于对接和分子动力学模拟的先进小分子激酶抑制剂鉴定let-7前miRNA结合物的分析。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2025-07-09 DOI: 10.1002/cbic.202500421

Soma Roy, Yang Liu, Peng Wu

{"title":"Docking and Molecular Dynamics Simulation-Based Analysis of Advanced Small-Molecule Kinase Inhibitors Identified pre-let-7 miRNA Binders.","authors":"Soma Roy, Yang Liu, Peng Wu","doi":"10.1002/cbic.202500421","DOIUrl":"10.1002/cbic.202500421","url":null,"abstract":"RNAs play crucial roles in various cellular actions, and the uncontrolled expression or improper folding of RNAs is a cause of many diseases. Certain oncogenic phenotypes stem from the overexpression of regulatory microRNAs that contain secondary structural elements. Thus, targeting disease-related microRNAs with small molecules is a potential therapeutic strategy that has attracted growing interest. To probe the RNA-binding chemical space held in advanced small-molecule therapeutics, in this work, we screened the 78 FDA-approved small-molecule kinase inhibitors (SMKIs) as representatives of the most advanced kinase inhibitors for their binding affinity with pre-let-7 miRNA via a combination of computational methods and biophysical measurement. The best-ranked SMKIs based on docking scores were subjected to molecular dynamics simulation studies, followed by analysis of different computational parameters. Collectively, it provided reliable information on the binding affinity for the top-performed SMKI in the formation of SMKI-miRNA complexes with pre-let-7. Furthermore, the identification of the predicted most promising SMKI-miRNA interactions was validated by microscale thermophoresis, measuring direct binding affinities. This study evaluating the binding landscapes of the 78 FDA-approved SMKIs with pre-let-7 miRNA served as an example highlighting the necessity to characterize the biological targets of SMKIs, many of which are FDA-approved cancer agents, at the transcriptomic level with RNAs. The study also illustrates the possibility that the interaction with RNA targets may contribute to the observed biological and clinical performance of these approved SMKIs.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500421"},"PeriodicalIF":2.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Internal Ubiquitin Electrophiles for Covalent Trapping and Inhibition of Deubiquitinases. 共价捕获和抑制去泛素酶的内部泛素亲电试剂。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2025-07-08 DOI: 10.1002/cbic.202500318

Nipuni M Pannala, Rishi S Patel, Abhijith Saseendran Anit, Debapriya Bhattacharya, Kristos Negron Teron, Bryon Drown, Rudi Fasan, Chittaranjan Das

{"title":"Internal Ubiquitin Electrophiles for Covalent Trapping and Inhibition of Deubiquitinases.","authors":"Nipuni M Pannala, Rishi S Patel, Abhijith Saseendran Anit, Debapriya Bhattacharya, Kristos Negron Teron, Bryon Drown, Rudi Fasan, Chittaranjan Das","doi":"10.1002/cbic.202500318","DOIUrl":"10.1002/cbic.202500318","url":null,"abstract":"The ubiquitin (Ub) system governs vital cellular processes in eukaryotic biology through an intricate network of Ub-protein interactions. While semisynthetic C-terminal Ub electrophiles (UbEs) are widely used to study Ub transfer and deubiquitinase (Dub) activity, they are limited to probing the active site while leaving other functionally important sites unexplored. Building on previously identified multivalent interaction interfaces and potential allosteric sites which are key to understanding their dynamic nature, here we report the development of genetically encoded Ub-based probes to covalently tether Ub-protein interactions in a proximity-driven manner at distal locations away from the active site. This study demonstrates that UbEs with internal electrophiles maintain conformational changes observed with their C-terminal counterparts while circumventing their limitations in capturing distal binding-site complexes, an emerging feature in Ub-mediated regulation. Genetically encoding these electrophiles further demonstrate rational variation as activity-based probes (ABP), leading to a Met1-diUb ABP showing preference for OTULIN over other Met1 cleaving Dubs. Taken together, our study introduces genetically encoded Ub-based probes to explore the structural and biochemical significance of Ub-Dub interactions beyond the canonical S1 site, overcoming some limitations of traditional Ub C-terminal electrophiles.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500318"},"PeriodicalIF":2.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Developing FGF2 Mutants with Selectively Reduced Heparan Sulfate Affinity to Explore Their Impact on FGFR1 Signaling. 选择性降低硫酸肝素亲和力的FGF2突变体研究其对FGFR1信号传导的影响

IF 2.6 4区生物学

ChemBioChem Pub Date : 2025-07-08 DOI: 10.1002/cbic.202500353

Yuga Okada, Akihiro Eguchi, Daisuke Kuroda, Kouhei Tsumoto, Ryosuke Ueki, Shinsuke Sando

{"title":"Developing FGF2 Mutants with Selectively Reduced Heparan Sulfate Affinity to Explore Their Impact on FGFR1 Signaling.","authors":"Yuga Okada, Akihiro Eguchi, Daisuke Kuroda, Kouhei Tsumoto, Ryosuke Ueki, Shinsuke Sando","doi":"10.1002/cbic.202500353","DOIUrl":"https://doi.org/10.1002/cbic.202500353","url":null,"abstract":"Fibroblast growth factor 2 (FGF2) regulates signal transduction by forming complexes with its receptors, FGF receptors (FGFRs), and heparan sulfate (HS), playing a crucial role in biological systems. Although HS has been suggested to modulate FGF/FGFR signaling as a co-receptor, multiple hypotheses exist regarding how HS affects FGF/FGFR signaling, and the mechanism remains unclear. In this study, to highlight the role of FGF2/HS interaction in FGF2/FGFR1 signaling, FGF2 mutants with reduced HS-binding affinity were rationally designed through in silico analysis. These FGF2 mutants exhibited reduced HS affinity by more than two orders of magnitude while maintaining binding affinity to FGFR1. In addition, these mutants retained their thermal stability. Cellular assays using the FGF2 mutant suggested that, contrary to previous reports, the contribution of the FGF2/HS interaction in FGF2/FGFR1 signaling may be limited. The mutant FGFs that specifically alter the interaction with HS, achieved in this study, would contribute to an understanding of the role of FGF/HS interaction in FGF/FGFR signaling.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500353"},"PeriodicalIF":2.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design and Characterization of Prodrugged Anti-CTLA-4 Antibodies. 前药抗ctla -4抗体的设计与表征。

IF 2.6 4区生物学

ChemBioChem Pub Date : 2025-07-08 DOI: 10.1002/cbic.202500304

Sayumi Yamazoe, Mary Huber, Srikanth Kotapati, Rahima Akter, Aarti Jashnani, Suprit Deol, Christine Bee, John Engelhart, Yam B Poudel, Stanley Krystek, Mohan Srinivasan, Arvind Rajpal, Yong Zhang, Pavel Strop, Chetana Rao, John Haugner

{"title":"Design and Characterization of Prodrugged Anti-CTLA-4 Antibodies.","authors":"Sayumi Yamazoe, Mary Huber, Srikanth Kotapati, Rahima Akter, Aarti Jashnani, Suprit Deol, Christine Bee, John Engelhart, Yam B Poudel, Stanley Krystek, Mohan Srinivasan, Arvind Rajpal, Yong Zhang, Pavel Strop, Chetana Rao, John Haugner","doi":"10.1002/cbic.202500304","DOIUrl":"https://doi.org/10.1002/cbic.202500304","url":null,"abstract":"Therapeutic antibodies are widely used to treat diseases like cancer and inflammatory conditions by binding with high specificity to their molecular targets. Masking is a strategy to mitigate undesirable activity in non-target tissues, improving safety and pharmacokinetic (PK) profiles by reducing target-mediated drug disposition (TMDD). In this study, we explored masking an anti-CTLA-4 antibody by conjugating a large PEG molecule to specific sites on the antibody. While anti-CTLA-4 immunotherapy benefits solid tumor treatment, its adverse events limit its utility. We evaluated multiple conjugation sites within the complementarity-determining regions (CDRs) and adjacent framework regions to attenuate CTLA-4 binding. We identified the optimal site for maximizing masking efficiency, allowing for efficient bioconjugation and functional restoration upon exposure to a cleaving enzyme in the tumor microenvironment. The prodrugged antibody exhibited reduced binding to CTLA-4 and Fc gamma receptors (FcgRs), high stability, and an extended half-life in a mouse model. This technology has the potential to improve the PK profile and safety attributes of therapeutic antibodies.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500304"},"PeriodicalIF":2.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Local and Global Behavior of Unfolded and Intrinsically Disordered Peptides and Proteins 未折叠和内在无序肽和蛋白质的局部和全局行为。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2025-07-04 DOI: 10.1002/cbic.202500172

Reinhard Schweitzer-Stenner

引用次数: 0

Covalent Stabilization of Collagen Mimetic Triple Helices and Assemblies by Dopa Crosslinking. 多巴交联法稳定拟胶原三螺旋和组装的共价。

IF 2.6 4区生物学

ChemBioChem Pub Date : 2025-07-03 DOI: 10.1002/cbic.202500268

Carson Cole, Brett H Pogostin, Vardan H Vardanyan, Kiana A Cahue, Thi H Bui, Adam C Farsheed, Joseph W R Swain, Jonathan Makhoul, Marija Dubackic, Peter Holmqvist, Ulf Olsson, Anatoly B Kolomeisky, Kevin J McHugh, Jeffrey Dale Hartgerink

{"title":"Covalent Stabilization of Collagen Mimetic Triple Helices and Assemblies by Dopa Crosslinking.","authors":"Carson Cole, Brett H Pogostin, Vardan H Vardanyan, Kiana A Cahue, Thi H Bui, Adam C Farsheed, Joseph W R Swain, Jonathan Makhoul, Marija Dubackic, Peter Holmqvist, Ulf Olsson, Anatoly B Kolomeisky, Kevin J McHugh, Jeffrey Dale Hartgerink","doi":"10.1002/cbic.202500268","DOIUrl":"https://doi.org/10.1002/cbic.202500268","url":null,"abstract":"Creating thermally stable collagen mimetic peptides (CMPs) is a persistent challenge. Nature leverages covalent crosslinkings to stabilize collagen's triple helix and higher-order assemblies. Herein, we demonstrate that crosslinkings between levodopa (Dopa) and lysine can covalently stabilize the triple helix in collagen mimetic peptides. Since alkaline conditions catalyze the oxidation of the catechol on Dopa to a benzoquinone, while being in proximity to the nucleophilic lysine, we hypothesized that this reaction could be a facile method to covalently capture the supramolecular structure of CMPs by simply increasing the pH of the aqueous solvent with the addition of sodium hydroxide. This strategy covalently stabilizes CMP homotrimers and a de novo designed ABC-type heterotrimer demonstrating that the Lysine-Dopa covalent bond is best templated by a supramolecular, axial cation-π pairwise interaction. In nature, collagen can hierarchically assemble into fibers. This behavior can be mimicked with the self-assembly of CMPs, but the resulting nanofibers typically exhibit thermal stability below body temperature. In a final application, we demonstrate that Dopa-Lysine covalent capture also enhances the thermal stability of CMP nanofibers well above 37 °C. This biomimetic covalent capture strategy can stabilize a wide variety of CMP systems and potentially enable the biomedical application of these materials.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500268"},"PeriodicalIF":2.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Adding A C-Terminal Amino Acid Prevents the Conformational Interconversion of Plecantide Analogs. 添加一个c端氨基酸可以阻止多聚糖类似物的构象相互转换。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2025-07-02 DOI: 10.1002/cbic.202500237

Yi Zhou, Jingyan Jin, Pingzheng Zhou, Wu Su, Guiyang Yao

引用次数: 0

Exploring the Substrate Flexibility of GrsB Thioesterase Leads to the Structural Reassignment of a Gramicidin S Variant. 探索GrsB硫酯酶的底物灵活性导致Gramicidin S变体的结构重分配。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2025-07-02 DOI: 10.1002/cbic.202500412

Sho Konno, Tomoe Mizuguchi, Atsuko Suzuki, Miyu Tanaka, Fumihiro Ishikawa, Akihiro Taguchi, Atsuhiko Taniguchi, Genzoh Tanabe, Yoshio Hayashi

{"title":"Exploring the Substrate Flexibility of GrsB Thioesterase Leads to the Structural Reassignment of a Gramicidin S Variant.","authors":"Sho Konno, Tomoe Mizuguchi, Atsuko Suzuki, Miyu Tanaka, Fumihiro Ishikawa, Akihiro Taguchi, Atsuhiko Taniguchi, Genzoh Tanabe, Yoshio Hayashi","doi":"10.1002/cbic.202500412","DOIUrl":"10.1002/cbic.202500412","url":null,"abstract":"Gramicidin S (GS) is a cyclic decapeptide derived from two pentapeptides. The C-terminal thioesterase (TE) domain of gramicidin S synthetase B (GrsB) dimerizes precursor pentapeptides and cyclizes the resulting linear decapeptide. Recently, a GS variant (GS-SA), in which a single D-Phe is replaced by L-Ser(Allyl), is reported via precursor-directed biosynthesis in a native GS producer. To understand how GrsB-TE processes such modified precursors, its substrate specificity using synthetic linear peptides is investigated. GrsB-TE cyclizes a substrate containing L-Ser(Allyl) at position 6 but not at position 1. However, the enzymatically synthesized GS-SA shows a different high-performance liquid chromatography retention time than that of the reported GS variant. Further structural and functional analyses, including 1H nuclear magnetic resonance, antimicrobial assays, and circular dichroism spectroscopy, reveal that the reported GS-SA contained D-Ser(Allyl) rather than L-Ser(Allyl). These findings reveal a previously unrecognized stereochemical flexibility in GrsB-TE and support the structural revision of the reported GS variant.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500412"},"PeriodicalIF":2.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Photo-Triggered Hyaluronic Acid Hydrogel for 3D Culture and Cell Recovery. 光触发透明质酸水凝胶用于三维培养和细胞恢复。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2025-07-02 DOI: 10.1002/cbic.202500310

Francesco Palmieri, Marième Gueye, Lucia Vicario Del Rio, Saskia Bunschuh, Pradeep Chopra, Silvia Mihăilă, Tina Vermonden, Riccardo Levato, Geert-Jan Boons

{"title":"Photo-Triggered Hyaluronic Acid Hydrogel for 3D Culture and Cell Recovery.","authors":"Francesco Palmieri, Marième Gueye, Lucia Vicario Del Rio, Saskia Bunschuh, Pradeep Chopra, Silvia Mihăilă, Tina Vermonden, Riccardo Levato, Geert-Jan Boons","doi":"10.1002/cbic.202500310","DOIUrl":"10.1002/cbic.202500310","url":null,"abstract":"Properties of semisynthetic hydrogels can be fine-tuned, making these attractive for various applications in regenerative medicine. Herein, a hydrogel platform based on hyaluronic acid (HA) modified by (1R, 8S,9S)-bicycle[6.1.0]non-4-yn-9-ylmethanol (BCN) and a cross-linker composed of light-sensitive o-nitrobenzyl and polyethylene glycol (PEG) chains terminating in azides is described. The two components can undergo strain-promoted azide-alkyne cycloaddition resulting in rapid gel formation. First, adipose-derived mesenchymal stromal cells (MSCs) are incorporated in the hydrogel and it is demonstrated that the cells can be easily retrieved by UV light-mediated degradation, maintaining viability and retaining spindle-like shape when the cells are replated. Next, a proof-of-concept of inducing light-mediated softening of the hydrogel to modulate the morphology of the encapsulated cells is provided. A co-culture of endothelial cells (cord blood-derived endothelial colony forming cells and bone marrow-derived MSCs), which is commonly studied for their ability to form capillary-like vascular networks, is cultured in the regular and light-induced softened hydrogels. Nonphotoexposed hydrogels show cells with a prevalently rounded morphology, whereas stretched cells connecting into a primitive capillary network are observed in the light-softened hydrogels. Photo-induced softening offers potential to locally control cell shape and self-organization capacity.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500310"},"PeriodicalIF":2.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0