ChemBioChem最新文献_第2页

Covalent Ligands that Target the Human Papillomavirus E6 Oncoprotein 靶向人乳头瘤病毒E6癌蛋白的共价配体。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-11-05 DOI: 10.1002/cbic.70590

Charlotte M. Zammit, Daniel K. Nomura

{"title":"Covalent Ligands that Target the Human Papillomavirus E6 Oncoprotein","authors":"Charlotte M. Zammit, Daniel K. Nomura","doi":"10.1002/cbic.70590","DOIUrl":"10.1002/cbic.70590","url":null,"abstract":"The high-risk human papillomavirus (HPV) early protein 6 (E6) viral oncoprotein is a key player in HPV-mediated cancers and is the major driver of cervical, anal, and a substantial portion of head and neck cancers. HPV E6 recruits the cellular ubiquitin E3-ligase E6-associated protein (E6AP), also termed UBE3A, and this E6/E6AP complex in turn recruits the tumor suppressor p53, resulting in the ubiquitin-mediated degradation of p53. The cysteine-rich E6 protein presents an attractive target for chemical intervention through covalent, cysteine-reactive chemistries. While previous studies have uncovered peptidic covalent inhibitors of E6, we sought to determine whether we could identify nonpeptidic functional binders. We screened a library of cysteine-reactive covalent ligands and identified a pyrazoline hit, EN218, bearing a chloroacetamide cysteine-reactive warhead. Evaluation of pyrazoline analogs led to the development of an improved molecule, (S)-WX48A, that stereoselectively reacted with C58 on E6 to inhibit E6-mediated p53 ubiquitination. While this molecule is still in an early stage and requires further medicinal chemistry optimization to exert on-target cellular activity, our study demonstrates that E6 can be directly and stereoselectively targeted with a covalent nonpeptidic small-molecule and provides a foundation for developing more drug-like E6 inhibitors for HPV therapy.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 21","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149331815","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

Beyond Static Structures: New Opportunities to Model the Dynamic Interactions of Cell-Surface Proteins 超越静态结构：模拟细胞表面蛋白质动态相互作用的新机会。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-10-30 DOI: 10.1002/cbic.70592

Yinghao Wu

引用次数: 0

Exploring the Chemistry, Biological Mechanisms, and Therapeutic Potential of Squalamine and Trodusquemine 探索角鲨胺和卓杜喹明的化学、生物学机制和治疗潜力。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-10-30 DOI: 10.1002/cbic.70582

Antoine Hivert, Fabienne Neulat-Ripoll, Jean Michel Bolla, Jean Michel Brunel

引用次数: 0

A Role for Janus Cyclohexyl Ring Motifs in Medicinal Chemistry. Incorporation Into G-Quadruplex Ligands and Anti-Trypanosoma brucei Activity Janus环己基基在药物化学中的作用。g -四联体配体的掺入及抗布氏锥虫活性研究

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-10-30 DOI: 10.1002/cbic.70588

Josephine M. Stewart, Mario Kehler, Vytautas Kuodis, Gary N. Parkinson, Wenqian Chen, Terry K. Smith, Zoë A. E. Waller, David O’Hagan

{"title":"A Role for Janus Cyclohexyl Ring Motifs in Medicinal Chemistry. Incorporation Into G-Quadruplex Ligands and Anti-Trypanosoma brucei Activity","authors":"Josephine M. Stewart, Mario Kehler, Vytautas Kuodis, Gary N. Parkinson, Wenqian Chen, Terry K. Smith, Zoë A. E. Waller, David O’Hagan","doi":"10.1002/cbic.70588","DOIUrl":"10.1002/cbic.70588","url":null,"abstract":"The naphthalene diimide (NDI) ring system is recognized as a privileged motif for binding to G-quadruplex DNA. Accordingly, compounds with peripheral groups attached to the NDI core are being explored as antiparasitic and anticancer candidates. In this study, we have synthesized and explored a series of NDIs with peripheral all-cis ring fluorinated cyclohexyl rings to assess their relative stabilization potential for G-quadruplex and double-stranded DNA. This was explored through FRET melting experiments and measuring changes in melting temperatures (ΔTm). Compounds were also assayed against Trypanosoma brucei to assess their in vitro potency (EC50) against the causative parasite of human African trypanosomiasis or African Sleeping Sickness. The study revealed significant differences in activity when changing the nature of fluorine substitutions on the cyclohexane ring and also the length and nature (ether (O) or methylene (CH2)) of the linker to the core aromatic motif. The most active compound of the series was ether 12a which displayed nanomolar activity (EC50 = 40 nM) against T. brucei although with a modest selectivity (14-fold) for the parasite over HeLa (human model) cells. The study reveals good prospects for exploring fluorinated Janus cyclohexanes in a medicinal chemistry context.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 21","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.70588","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Expression of Human CYP2D6 in Artificial Cells Based on Polymer-Lipid Hybrid Vesicles 基于聚脂杂交囊泡的人CYP2D6在人工细胞中的表达

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-10-30 DOI: 10.1002/cbic.70572

Sarah Dahl, Paula De Dios Andres, Grégory Beaune, Jaakko V. I. Timonen, James Behrendorff, Kirill Alexandrov, Wayne Johnston, Brigitte Städler

{"title":"Expression of Human CYP2D6 in Artificial Cells Based on Polymer-Lipid Hybrid Vesicles","authors":"Sarah Dahl, Paula De Dios Andres, Grégory Beaune, Jaakko V. I. Timonen, James Behrendorff, Kirill Alexandrov, Wayne Johnston, Brigitte Städler","doi":"10.1002/cbic.70572","DOIUrl":"10.1002/cbic.70572","url":null,"abstract":"Artificial cells with the ability to express functional, biomedically relevant enzymes have long been a goal in the field of bottom-up synthetic biology. Here, we demonstrate the expression of human cytochrome P450 2D6 (CYP2D6) within the lumen of giant hybrid vesicle-based artificial cells using a cell-free protein expression system based on the protozoan Leishmania tarentolae. The vesicle membranes comprise 1,2-dioleoyl-sn-glycero-3-phosphocholine and amphiphilic block copolymers containing poly(cholesteryl methacrylate-co-butyl methacrylate) with either poly(galactose methacrylate) (pGalacMA) or poly(carboxyethyl acrylate) as the hydrophilic block. The amount and composition of the block copolymer incorporated into the giant hybrid vesicle membrane altered the artificial cells’ ability to support functional protein expression, likely through changes in membrane properties. In particular, giant hybrid vesicles containing pGalacMA supported production of enzymatically active CYP2D6. Overall, the reported approach advances the development of artificial cells capable of producing functional, biomedically relevant enzymes. Further, the effort highlights complex interplay between polymer properties and performance of biological components in the functional complexity achievable in polymer-lipid hybrid vesicles.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 21","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.70572","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterization and Molecular Engineering of a Thermostable Amino Acid Dehydrogenase for Enhanced (S)-2-Amino-1-Butanol Synthesis 一种增强(S)-2-氨基-1-丁醇合成的耐热氨基酸脱氢酶的表征及分子工程。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-10-28 DOI: 10.1002/cbic.70514

Shiyu Wei, Dantong Feng, Zhen Yang, Zeqing Wang, Li Chen, Xiaofeng Ji, Yali You, Ci Song, Yali Wang, Ying Li, Yanli Zheng, Wangshan Zheng, Yan Leng, Yongqiang Tian

{"title":"Characterization and Molecular Engineering of a Thermostable Amino Acid Dehydrogenase for Enhanced (S)-2-Amino-1-Butanol Synthesis","authors":"Shiyu Wei, Dantong Feng, Zhen Yang, Zeqing Wang, Li Chen, Xiaofeng Ji, Yali You, Ci Song, Yali Wang, Ying Li, Yanli Zheng, Wangshan Zheng, Yan Leng, Yongqiang Tian","doi":"10.1002/cbic.70514","DOIUrl":"10.1002/cbic.70514","url":null,"abstract":"(S)-2-Amino-1-butanol, a key intermediate for ethambutol hydrochloride synthesis, is currently produced via heavy metal-catalyzed processes or enzymatic resolution with limited theoretical yields. While amine dehydrogenases (AmDHs) offer sustainable alternatives for asymmetric reductive amination, their applicability is often restricted by narrow substrate scope. Here, we report the discovery of a thermostable amino acid dehydrogenase from Thermoactinomyces daqus (TdAADH) that exhibits optimal activity at pH 9.0 and 55 °C with exceptional thermostability (t1/2 = 21 days at 40 °C). Although inactive toward the non-native substrate 1-hydroxy-2-butanone, structure-guided engineering via site-directed and iterative saturation mutagenesis (ISM) successfully endowed the enzyme with desired functionality: the initial double mutant K93S/N288L (M1) acquired de novo amination activity, while subsequent evolution to the quintuple mutant M4 (incorporating L136T/T139D/M141R) enhanced specific activity by 2.75-fold (5.38 U·g−1) without compromising enantioselectivity (ee > 99%). Mechanistic investigations via molecular docking suggest that these mutations plausibly reshape the substrate-binding pocket, alleviate steric hindrance, and optimize electrostatic interactions to accommodate the hydroxyketone substrate. Preparative-scale biotransformation (40 °C, 30 mM substrate, coupled with GDH/glucose for cofactor recycling) achieved quantitative conversion (≥99%) within 36 h. This work expands the enzymatic toolbox for thermostable AmDHs.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 21","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284349","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

The Dual Nature of RNA Ligation and Degradation by T4 RNA Ligase 1: Insights Into an AMP-Driven, Nucleobase-Dependent Reverse Reaction RNA连接和T4 RNA连接酶1降解的双重性质：对amp驱动，核碱基依赖的逆反应的见解。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-10-28 DOI: 10.1002/cbic.70559

Nozomi Adachi, Wataru Takahagi, Shohei Terazawa, Ryoji F. Abe, Nao Masuda, Kosuke Fujishima

{"title":"The Dual Nature of RNA Ligation and Degradation by T4 RNA Ligase 1: Insights Into an AMP-Driven, Nucleobase-Dependent Reverse Reaction","authors":"Nozomi Adachi, Wataru Takahagi, Shohei Terazawa, Ryoji F. Abe, Nao Masuda, Kosuke Fujishima","doi":"10.1002/cbic.70559","DOIUrl":"10.1002/cbic.70559","url":null,"abstract":"T4 RNA Ligase 1 (Rnl1) catalyzes the ligation of a 5′-phosphate to a 3′-hydroxyl in single-stranded RNA and is widely used in RNA biotechnology for applications such as RNA library preparation and 3′-adapter ligation. In addition to ligation reaction, Rnl1 catalyzes the reverse reaction, leading to RNA degradation. However, how RNA sequence affects susceptibility to this reverse reaction remains unclear, and practical strategies for controlling it through buffer conditions have not been established. Previous studies showed that AMP promotes and ATP suppresses the reverse reaction; we confirmed these effects by electrophoretic analysis of FAM-labeled RNA homopolymers, a substrate not previously examined. Furthermore, using miRNA substrates, we demonstrated that the reverse reaction can occur under conditions that more closely resemble the practical conditions in which Rnl1 is used, thereby extending the relevance of previous findings. Additionally, we showed that the Rnl1-mediated reverse reaction exhibits pronounced nucleobase preference. The reverse reaction is suppressed by elevated temperature and duplex formation. Furthermore, experimental results combined with stochastic simulations indicate that Rnl1-mediated degradation proceeds via an endonucleolytic mechanism. These findings define how reaction conditions and nucleobase difference influence reverse reaction efficiency and provide practical guidance for minimizing RNA degradation while maintaining ligation efficiency.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 21","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13717052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of Highly Efficient Lysosome-Targeting Peptide Ligands for the Internalization of Extracellular Proteins 细胞外蛋白内化高效溶酶体靶向肽配体的开发。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-10-28 DOI: 10.1002/cbic.70587

Yuan Zhao, Yaxian Liao, Xuankun Chen, Deqin Cai, Regina Stasser de Gonzalez, Hua Tang, Florence M. Brunel, Nick Cox, Joseph Stock, Guangsen Fu, Alexander N. Zaykov, Weiping Tang

{"title":"Development of Highly Efficient Lysosome-Targeting Peptide Ligands for the Internalization of Extracellular Proteins","authors":"Yuan Zhao, Yaxian Liao, Xuankun Chen, Deqin Cai, Regina Stasser de Gonzalez, Hua Tang, Florence M. Brunel, Nick Cox, Joseph Stock, Guangsen Fu, Alexander N. Zaykov, Weiping Tang","doi":"10.1002/cbic.70587","DOIUrl":"10.1002/cbic.70587","url":null,"abstract":"Lysosome-targeting chimeras (LYTACs) induce the internalization of extracellular and membrane-associated proteins by routing them to lysosomes via endogenous receptors, such as the insulin-like growth factor-2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor. While current IGF2R ligands are effective, expanding the LYTAC toolkit with structurally simple and synthetically accessible ligands remains a practical necessity. Here, we first validated that previously reported dimeric and monomeric peptides induce robust internalization, establishing them as effective IGF2R-targeting LYTAC ligands. To further optimize the peptide architecture, we performed systematic mutational scanning on its monomeric sequence to simplify the peptide architecture. We identified the L4 variant, which features a single leucine substitution at the fourth position. This optimized monomer induces greater internalization efficiency than the previously reported wild-type monomeric peptide ligand. To demonstrate its utility, we conjugated the L4 recruiter to a specific PCSK9 binder. The resulting bifunctional molecule successfully induced the dose- and time-dependent internalization of PCSK9. Collectively, these findings establish several peptide variants as practical and highly effective building blocks for the development of extracellular protein internalization platforms.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 21","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13717051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Explorations of the Hydrogenation of D2 by Nitrogenase 氮化酶对D2加氢反应的探索。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-10-28 DOI: 10.1002/cbic.70570

Ian Dance

引用次数: 0

Vitamin B12-Functionalized Nanogels for pH-, and Redox-Responsive Doxorubicin Delivery 用于pH和氧化还原反应的维生素b12功能化纳米凝胶递送阿霉素

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-10-26 DOI: 10.1002/cbic.70580

Serife Dagdelen, Paula D. Mestizo, Marcin Mackiewicz, Agnieszka Kurdyn, Ewa Augustin, Marcin Karbarz, Felix Zelder

{"title":"Vitamin B12-Functionalized Nanogels for pH-, and Redox-Responsive Doxorubicin Delivery","authors":"Serife Dagdelen, Paula D. Mestizo, Marcin Mackiewicz, Agnieszka Kurdyn, Ewa Augustin, Marcin Karbarz, Felix Zelder","doi":"10.1002/cbic.70580","DOIUrl":"https://doi.org/10.1002/cbic.70580","url":null,"abstract":"Rapidly proliferating cancer cells display an elevated demand for vitamin B12, rendering this bacterial-derived cofactor an attractive targeting motif for nanotherapeutic drug delivery. Herein, we report a concise two-step synthesis of a polymerizable 5′-modified vitamin B12 -monomer that enables the covalent integration of B12 into pH- and redox-responsive nanogels. The resulting nanogels efficiently encapsulate doxorubicin through electrostatic interactions between the cationic drug and the anionic nanogel network, while enabling stimuli-responsive drug release under tumor-relevant conditions. In vitro studies revealed that DOX@B12-nanogels retain potent antiproliferative activity against HT-29 colorectal cancer cells (IC50 = 0.878 ± 0.102 μM), while decreasing cytotoxicity toward healthy CCD 841 CoN cells by 34-fold relative to non-B12-functionalized control nanogels. These findings establish covalently engineered vitamin B12-nanogels as a promising platform for selective and stimuli-responsive anticancer drug delivery.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 20","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.70580","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0