ChemBioChem最新文献

{"title":"Advances in Hydrocarbon Stapled Peptides via Ring-Closing Metathesis: Synthetic Strategies, Structural Diversity, and Therapeutic Applications.","authors":"Linji Li, Rong Li, Yanan Jiang, Jingru Chao, Si Chen, Hongli Liao, Xiang Li","doi":"10.1002/cbic.202500527","DOIUrl":"https://doi.org/10.1002/cbic.202500527","url":null,"abstract":"<p><p>Peptide stapling has emerged as a powerful strategy to stabilize α-helical structures in peptides, thereby enhancing their proteolytic resistance, membrane permeability, and biological activity. Among the various stapling methodologies, hydrocarbon stapling via ruthenium-catalyzed ring-closing metathesis remains the most widely adopted due to its robust chemical efficiency and synthetic compatibility with solid-phase peptide synthesis. This review summarizes key advancements in hydrocarbon stapling technologies, including mono- and multiple-stapling, solution- and solid-phase approaches, and newer developments such as stitched and aza-stapled peptides. The integration of rigidified anchoring residues (e.g., cyclobutane or carbocyclic α, α-disubstituted amino acids) and orthogonal metathesis strategies has significantly expanded the structural diversity and functional potential of stapled peptides. Furthermore, novel bioorthogonal modifications and imaging capabilities, such as Raman-active diyne bridges, have opened new directions in therapeutic and diagnostic applications. Together, these innovations underscore the growing utility of stapled peptides in modulating protein-protein interactions and advancing peptide drug discovery.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500527"},"PeriodicalIF":2.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197478","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}

{"title":"5th Next Generation Biocatalysis Symposium (NextGenBiocat) in Milano, Italy.","authors":"Martina Letizia Contente, Fabio Parmeggiani","doi":"10.1002/cbic.202500550","DOIUrl":"https://doi.org/10.1002/cbic.202500550","url":null,"abstract":"<p><p>On May 8-9, 2025, the fifth edition of the NextGenBiocat symposium was held in Milano, Italy. The event has established itself as a key meeting point for the international scientific community engaged in the study of innovative enzymatic processes. The symposium aims to highlight the contributions of the next generation of researchers providing a dynamic and multidisciplinary forum to discuss the latest frontiers in biocatalysis.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500550"},"PeriodicalIF":2.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197555","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}

{"title":"Synthesis and Incorporation of a pH-Responsive Nucleoside Into DNA Sequences.","authors":"Eric Ogel, Sidney Becker","doi":"10.1002/cbic.202500650","DOIUrl":"https://doi.org/10.1002/cbic.202500650","url":null,"abstract":"<p><p>DNA's programable thermodynamics, structural versatility, and ease of synthesis makes it an ideal material for constructing molecular devices. While many biological systems are powered by proton gradients to drive dynamic processes, harnessing pH differences in DNA nanotechnology is possible through pH-responsive DNA motifs. Existing strategies, however, often depend on strict sequence constraints or nonphysiological pH conditions, limiting their applicability in complex DNA origami structures. In this article, a nucleoside with pH-sensitive base pairing is developed that reversibly switches its pairing specificity near physiological pH. This unnatural building block is recognized by standard polymerases, and its pairing behavior can be controlled by pH. Characterization of the base pairing properties reveals that duplex stability varies with pH, while canonical sequences remain unaffected. This design enables programable sequence motifs that transition between duplex and single-stranded DNA in response to pH changes. Our unnatural nucleoside therefore provides a versatile tool for dynamic DNA nanotechnology, with potential applications in DNA nanomachines, biosensing, and targeted drug delivery. Additionally, its physiological pK_a may enable general acid-base catalysis in ribozymes or DNAzymes, analogous to histidine in protein enzymes.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e70086"},"PeriodicalIF":2.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197558","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}

{"title":"Deserts, Rivers, Pools, and Billabongs: Water Features of the Nitrogenase Proteins, and their Functions.","authors":"Ian Dance","doi":"10.1002/cbic.202500541","DOIUrl":"https://doi.org/10.1002/cbic.202500541","url":null,"abstract":"<p><p>This review examines the occurrence and function of water inside the protein that contains the catalytic site of the enzyme nitrogenase. The requirement of 8 protons and 8 electrons to convert N₂ to NH₃ and the opposing acid-base character of reactant and product are unique in enzymology. The active site is an unprecedented iron sulfide cluster containing one heterometal, in Mo, V, and Fe isozymes. A key component supporting the complex chemical mechanism is water, which transports multiple exogenous protons, sequentially, and assists the egress of hydrophilic ammonia. Using high-resolution crystal structures of the nitrogenase isozymes and cryoEM data, I describe and classify all intraprotein water components. A singular property is the occurrence of extensive anhydrous domains that surround the reaction zone of the cofactor. This focuses attention on the proton supply chain, a river, along which protons are transferred by a Grotthuss mechanism from protein surface to cofactor. Another river, in an opposite direction, runs along the pathway for departing NH₃. I describe mechanisms for translocation of protons and of NH₃ and their use of water and homocitrate. Other water features buried in the proteins include a mechanistically significant single water molecule and featureless water pools.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500541"},"PeriodicalIF":2.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184365","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}

{"title":"Identification of Methylglyoxal Reactive Proteins with Photocaged Glycating Agents.","authors":"Saskia Sokoliova, I Raluca Sardaru, Franciszek P Warguła, Jos H Hermans, Hjalmar P Permentier, Peter L Horvatovich, Martin D Witte","doi":"10.1002/cbic.202500275","DOIUrl":"https://doi.org/10.1002/cbic.202500275","url":null,"abstract":"<p><p>Methylglyoxal is a highly reactive metabolite that is formed spontaneously in the glycolytic pathway. The side chains of various amino acid residues react with methylglyoxal to form advanced-glycation end products (AGEs). This enzyme-independent process introduces post-translational modifications onto the proteins and it is long thought that the resulting AGEs primarily inhibit proteins. More recent studies have shown that these AGEs can act in signaling and feedback loops and that a large number of proteins react reversibly with methylglyoxal. These findings lead to a renewed interest in methylglyoxal-induced AGEs and lead to the development of novel tools and methodologies that can be used to identify the modified proteins. Many of studies are nowadays still performed by adding methylglyoxal exogenously, often in a high concentration, despite the high reactivity of methylglyoxal. Herein, new photocaged-methylglyoxal derivatives are reported that allow the direct release of methylglyoxal in the sample of interest by irradiating the photocaged probe with UV light. It is shown that this labeling approach is more efficient. A far larger number of proteins are labeled with the photocaged probes than with the chemically activated probes. The here reported approach should allow studying in situ glycation under physiological more relevant conditions.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500275"},"PeriodicalIF":2.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184403","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}

{"title":"Five-In-One Antibacterial Strategy: A Mn(I) Complex Lights Up the Fight Against Tuberculosis.","authors":"Maryam Bashir, Md Kausar Raza","doi":"10.1002/cbic.202500529","DOIUrl":"https://doi.org/10.1002/cbic.202500529","url":null,"abstract":"<p><p>Tuberculosis, which the WHO describes as the \"world's top infectious killer,\" demands novel combating strategies rather than conventional ones, as the situation of Mycobacterium tuberculosis (Mtb) resistance to therapeutic drugs is continuous, leading to millions of deaths each year. In a recent study, Lai et al. report a manganese(I)-based photoactivatable carbon monoxide-releasing molecule (Mn-PTP) that unifies photodynamic therapy, transition metal reactivity, and carbon monoxide (CO) delivery into a single light-activated therapeutic platform. Upon white-light irradiation, Mn-PTP releases CO, generates both type I and type II reactive oxygen species (ROS), liberates a toxic antibacterial ligand (PTP), and forms catalytically active manganese oxides (MnO_x) species that decompose intracellular hydrogen peroxide (H₂O₂), thereby alleviating hypoxia and amplifying ROS generation. Mn-PTP demonstrates high selectivity for Mycobacterium smegmatis with, potent in vitro antibacterial activity (MIC₉₀ = 3.11 μM), robust biofilm disruption of M. smegmatis, and minimal cytotoxicity to normal cells. In in vivo, the compound significantly accelerates wound healing in infected mice, outperforming isoniazid. This highlight discusses Mn-PTP as a powerful \"one-for-all\" agent which, upon irradiation, releases five key components that, much like the five fingers through coordinated action, form a fist that effectively combats and eliminates bacterial infections, offering a powerful blueprint for next-generation metal-based therapeutics against persistent mycobacterial infections.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500529"},"PeriodicalIF":2.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190519","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}

{"title":"Development and Validation of a High-Throughput Screening Assay for the Legionella ADP-Ribosyl Transferase SdeA.","authors":"Halana C Vlaming, Vito Pol, Bjorn R van Doodewaerd, Angeliki Moutsiopoulou, Paul P Geurink, Robbert Q Kim, Gerbrand J van der Heden van Noort","doi":"10.1002/cbic.202500513","DOIUrl":"https://doi.org/10.1002/cbic.202500513","url":null,"abstract":"<p><p>Ubiquitination of proteins is one of the most crucial post-translational modifications in eukaryotic cells, typically involving conjugation of ubiquitin to a lysine residue in a substrate using a three-enzyme cascade that relies on ATP as energy source. The pathogen Legionella pneumophila, in contrast, employs a totally divergent pathway to ubiquitinate cellular host proteins in an unconventional manner that is crucial for bacterial proliferation. This multistep process is orchestrated by effector proteins from the SidE family which initially use NAD⁺ to adenosine diphosphate (ADP)-ribosylate ubiquitin in a mono-ADP-ribosyltransferase (mART) domain. The subsequent step relies on SidE phosphodiesterase activity to conjugate phosphoribosyl-Ubiquitin to serine residues in host substrates. Through these phosphoribosyl-ubiquitinating events, Legionella is able to gain local control over the host's ubiquitin system and simultaneously evades immune responses. Hence, pursuing new inhibitors which can disrupt these crucial steps in bacterial infection are essential towards further understanding and potentially blocking Legionella infection. Here, we present the application of an ε-NAD⁺ consumption-based fluorogenic assay to identify small molecule modulators of the SdeA effector enzyme in a High-Throughput Screening format, where over 600 compounds were screened. As a result, a potent inhibitor named cephalosporin C Zn²⁺ salt was discovered showing an IC₅₀ of 221 nM. To investigate the inhibitory properties more deeply, various cephalosporin analogs were synthesized where variations in charge and carbon length were introduced and their inhibitory efficiencies measured and compared. Our findings suggest that the inhibition is primarily attributed to the presence of the Zn²⁺ ion, rather than the cephalosporin core. We next compared the inhibitory potential of other bivalent metal ions, illustrating that the zinc ion causes the best inhibition of the Legionella effector.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500513"},"PeriodicalIF":2.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184419","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}

{"title":"Cryo-EM Structures Reveal Nonmirror-Image Binding of L- and D-Peptide Enantiomers at α7 Nicotinic Acetylcholine Receptor.","authors":"Ziyan Xu, Xiuxiu Cao, Tianqi Liu, Haopeng Chen, Sanling Liu, Changlin Tian, Demeng Sun","doi":"10.1002/cbic.202500599","DOIUrl":"https://doi.org/10.1002/cbic.202500599","url":null,"abstract":"<p><p>Peptides targeting the α7 nicotinic acetylcholine receptor (α7-nAChR) hold significant potential for biological research and therapeutic applications. Notably, linear D-amino acid peptides exhibit higher inhibitory potency against α7-nAChR and greater proteolytic stability compared to their L-type counterparts, making them more attractive candidates for both laboratory research and clinical use. However, the molecular basis of D-peptide binding to α7-nAChR remains elusive. Herein, cryo-EM structures of α7-nAChR is presented in complex with the L-peptide ^LKP1794 (2.68 Å) and its D-peptide enantiomer ^DKP1794 (2.53 Å), providing the first molecular insights into D-peptide recognition by α7-nAChR. Structural analysis reveals that both peptides occupy the orthosteric site of α7-nAChR. However, their binding poses are not merely mirror images; instead, they adopt a hybrid binding mode that combines mirror symmetry with a flipped peptide backbone orientation. Our structural data uncover a distinct D-peptide binding mechanism that diverges from the hypothesized retro-inversion model.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500599"},"PeriodicalIF":2.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184337","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}

{"title":"A Conversational Large-Language-Model Tutor that Accelerates Machine-Learning Method Development in Routine Bioanalytical Workflows.","authors":"An T H Le, Thomas Shvekher, Lewis Nguyen, Sergey N Krylov","doi":"10.1002/cbic.202500678","DOIUrl":"https://doi.org/10.1002/cbic.202500678","url":null,"abstract":"<p><p>As machine learning (ML) becomes increasingly relevant in experimental chemistry, many scientists face barriers to adoption due to limited training in ML. While AutoML platforms offer powerful capabilities, they lack the instructional scaffolding needed by users without an ML background. To address this gap, a lightweight, conversational assistant is presented that guides users through ML workflow design using plain-language dialog. Powered by OpenAI's GPT-4o and deployed via a Gradio interface, the assistant operates under a structured system prompt that simulates pedagogical reasoning. It behaves like a domain-specific tutor: helping users define ML goals, assess data structure, select models, evaluate metrics, and generate annotated Python code. A complete documentation of the development process is provided, allowing researchers to adapt the system for other domains. Herein, its utility is demonstrated in two representative case studies: 1) image classification of lateral flow immunoassay test strips for diagnostic readout; and 2) regression-based prediction of liquid chromatography-mass spectrometry retention times from molecular descriptors for small molecules. In both cases, lab members with no ML experience successfully developed working models guided solely by the assistant. By lowering the barrier to ML adoption in data-rich analytical workflows, this system offers a customizable workflow for building domain-specific assistants across experimental science.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500678"},"PeriodicalIF":2.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190493","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}

{"title":"Biocompatible Chemistry: A Plug-and-Play Toolbox for Chemical Biology Research.","authors":"Adam R Lovato, Zeng Lin, Qingfei Zheng","doi":"10.1002/cbic.202500590","DOIUrl":"10.1002/cbic.202500590","url":null,"abstract":"<p><p>Chemistry is referred to as the central science that has been widely applied in biological, material, and clinical research. Specifically, chemical biology is an interdisciplinary subject, where well-designed chemical tools and approaches are employed to solve complex biological questions. In the past few decades, the development of biocompatible reactions, which include click chemistry and bioorthogonal chemistry, is one of the most significant advances in the chemical biology field. In short, biocompatible chemistry enables the cleavage and formation of chemical bonds under physiological conditions, which can be thus utilized for specific labeling of cellular biomacromolecules of interest, biomarker/target validation, signaling pathway identification, drug discovery, and so on. The plug-and-play nature of biocompatible chemistry makes it a powerful toolbox for investigating complicated biological systems and producing drug leads for clinical usages. In this article, the commonly used biocompatible reactions and the recent advances of their representative applications in chemical biology research is summarized, thus highlighting the diverse potential of biocompatible chemistry as a plug-and-play toolbox for future basic and translational studies.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500590"},"PeriodicalIF":2.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147241","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}