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Effects of Clozapine on N-Methyl-D-Aspartate Glutamate Receptor-Related Amino Acids in the Rat Medial Prefrontal Cortex. 氯氮平对大鼠内侧前额皮质n -甲基- d -天冬氨酸受体相关氨基酸的影响。
IF 2.6 4区 生物学
ChemBioChem Pub Date : 2025-05-21 DOI: 10.1002/cbic.202500209
Masakazu Umino, Hiroshi Shiraku, Asami Umino, Yuji Kiuchi, Toru Nishikawa
{"title":"Effects of Clozapine on N-Methyl-D-Aspartate Glutamate Receptor-Related Amino Acids in the Rat Medial Prefrontal Cortex.","authors":"Masakazu Umino, Hiroshi Shiraku, Asami Umino, Yuji Kiuchi, Toru Nishikawa","doi":"10.1002/cbic.202500209","DOIUrl":"10.1002/cbic.202500209","url":null,"abstract":"<p><p>Clozapine is an atypical antipsychotic drug used for schizophrenia with treatment-refractory symptoms to other antipsychotics. Since a body of evidence indicates the involvement of the dysfunction of the N-methyl-D-aspartate type glutamate receptor (NMDAR) in the pathophysiology of antipsychotic-resistant and responsive symptoms of schizophrenia, we have evaluated the exact mechanisms underlying the superior clinical efficacy of clozapine by studying its effects on the extracellular signaling of NMDAR-related amino acids in the rat medial prefrontal cortex of freely moving rats using an in vivo dialysis technique. Intra-peritoneal injection of clozapine (5, 10 and 20 mg/kg) failed to affect the prefrontal extracellular levels of D-serine, a coagonist for the NMDAR acting at the glycine site, and its precursor, L-serine, from 20 to 160-min post-injection The cortical extracellular concentrations of glycine, another NMDAR coagonist, and L-arginine, a nitric oxide/NMDAR pathway-associated factor, were significantly reduced by 10 mg/kg of clozapine. Clozapine administration (20 mg/kg) elevated the prefrontal extracellular levels of L-glutamate (P < 0.027 by pairwise comparison with saline-injected controls), which was not statistically significant after multiple comparisons. The present findings support the view that clozapine could influence the NMDAR function, at least in part, through modulation of the prefrontal extracellular concentrations of glycine, L-arginine and/or L-glutamate.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500209"},"PeriodicalIF":2.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109068","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
Methods for Controlling Small GTPase Activity. 控制小GTPase活性的方法。
IF 2.6 4区 生物学
ChemBioChem Pub Date : 2025-05-21 DOI: 10.1002/cbic.202500156
Benjamin Faulkner, Yuchen He, Daniel Sitrin, Cliff I Stains
{"title":"Methods for Controlling Small GTPase Activity.","authors":"Benjamin Faulkner, Yuchen He, Daniel Sitrin, Cliff I Stains","doi":"10.1002/cbic.202500156","DOIUrl":"10.1002/cbic.202500156","url":null,"abstract":"<p><p>Small GTPases comprise a diverse class of signaling proteins in mammalian cells and regulate a variety of cellular processes such as cell growth, cell movement, vesicle formation, and nuclear transport. Due to their involvement in critical cellular pathways, changes in the activation state of small GTPases due to genetic mutations or alterations in gene expression can lead to human diseases. As such, the ability to control the activity of small GTPases is paramount in understanding the precise role these proteins play in human biology and in reducing their impacts on related diseases. Herein, important advances made in the development of small-molecule- and protein engineering-based strategies to control the activity of small GTPases are presented. Current approaches within each area are discussed within their historical contexts along with commentary on the importance that each technology has had on improving the ability to regulate small GTPase activity. Given this ever-evolving toolbox for controlling small GTPase signaling, continued growth in the study of this protein class is anticipated.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500156"},"PeriodicalIF":2.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109069","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
Peptidomimetics Targeting the Amyloidogenicity of Nucleophosmin 1 Mutations in Acute Myeloid Leukemia. 靶向急性髓系白血病中核磷蛋白1突变淀粉样变性的拟肽物。
IF 2.6 4区 生物学
ChemBioChem Pub Date : 2025-05-21 DOI: 10.1002/cbic.202500306
Daniele Florio, Sara La Manna, Giada Raffaella Fiore, Valentina Roviello, Giuliano Castellano, Sossio Fabio Graziano, Anna Maria Malfitano, Daniela Marasco
{"title":"Peptidomimetics Targeting the Amyloidogenicity of Nucleophosmin 1 Mutations in Acute Myeloid Leukemia.","authors":"Daniele Florio, Sara La Manna, Giada Raffaella Fiore, Valentina Roviello, Giuliano Castellano, Sossio Fabio Graziano, Anna Maria Malfitano, Daniela Marasco","doi":"10.1002/cbic.202500306","DOIUrl":"10.1002/cbic.202500306","url":null,"abstract":"<p><p>Nucleophosmin 1(NPM1) is an abundant human protein endowed with many functions where whose dysregulation leads to various cancers and mutations are relevant in acute myeloid leukemia (AML). In the wild-type form, pentameric NPM1 resides mainly in the nucleolus even if it shuttles toward the cytosol exerting its chaperon function; conversely in AML-mutated versions, it has mainly a cytoplasmic localization, hence the name NPMc+. All types of AML mutations determine an important amyloid aggregation propensity of the C-terminal domains (CTD) of NPMc+ and to exploit this amyloidogenicity for therapeutical purposes; herein, this study presents the design and structural and functional investigations of a series of peptides analogs of the sequence of the second helix of the three-helix bundle of the wt CTD as potential enhancers of amyloid aggregation. Peptides are designed by introducing conservative mutations in the native 264-277 fragment, and their structural features and amyloid propensities are assessed through ThT fluorescence, circular dichroism spectroscopies and scanning electron microscopy. Several \"accelerator sequences\" are employed in amyloid seeding assays (ASAs): The sequence NPM1<sub>264-277</sub> K<sub>267</sub>R, with the single mutation Lys<sup>267</sup>/Arg, exhibits the greater ability to act as a promoter of the amyloid aggregation of NPM1<sub>264-277</sub>, limiting its toxicity and rescuing cell viability in OCI-AML3 cells.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500306"},"PeriodicalIF":2.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118437","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
Designing the Proteome with Chemical Tools: Degrons and Beyond. 用化学工具设计蛋白质组:Degrons及其他。
IF 2.6 4区 生物学
ChemBioChem Pub Date : 2025-05-21 DOI: 10.1002/cbic.202500345
Laurence John Seabrook, Catherine Ramirez Livelo, Lauren Veronica Albrecht
{"title":"Designing the Proteome with Chemical Tools: Degrons and Beyond.","authors":"Laurence John Seabrook, Catherine Ramirez Livelo, Lauren Veronica Albrecht","doi":"10.1002/cbic.202500345","DOIUrl":"https://doi.org/10.1002/cbic.202500345","url":null,"abstract":"<p><p>Cell biology relies on precise changes in protein stability, which can be chemically harnessed to transform cell fate. Decades of research have revealed the many intricate systems underlying cellular proteostasis, which can be hijacked by proximity-based degrader compounds. The archetypal degrader, PROteolysis TArgeting Chimera (PROTAC), recruits E3 ligases to protein targets to facilitate their ubiquitination and degradation in the proteasome. Being able to customize the human proteome with chemical tools has great value for fundamental research and for clinical progress through the controlled elimination of disease-causing proteins. Success within the degrader field has reinvigorated interest in mapping the mechanisms underlying native protein degradation, which has platformed new degrader classes capable of advancing the field towards the goal of degrading the entire human proteome. This review discusses ongoing strategies to identify degrons regulating native protein turnover, advances in chemical tools to activate these degrons, and new attempts to streamline degron pathways for simplified targeted protein degradation. The continued discovery and application of degrons has the power to transform human biology and combat disease.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e202500345"},"PeriodicalIF":2.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118430","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
Synthesis of Nucleoside Derivatives by Biomimetic Ester Migration. 仿生酯迁移法合成核苷衍生物。
IF 2.6 4区 生物学
ChemBioChem Pub Date : 2025-05-21 DOI: 10.1002/cbic.202500395
Nathalie J Kurrle, Christoph J B Seifert, Nathalie Hampel, Tamara Rauch, Michael Thoma, Luca V Parziale, Marian S R Ebeling, Dino Berthold, Oliver Trapp
{"title":"Synthesis of Nucleoside Derivatives by Biomimetic Ester Migration.","authors":"Nathalie J Kurrle, Christoph J B Seifert, Nathalie Hampel, Tamara Rauch, Michael Thoma, Luca V Parziale, Marian S R Ebeling, Dino Berthold, Oliver Trapp","doi":"10.1002/cbic.202500395","DOIUrl":"10.1002/cbic.202500395","url":null,"abstract":"<p><p>Modified nucleosides play important roles as agents in medicinal chemistry due to their anti-inflammatory, antiviral, and antiproliferative properties, as well as in biochemical processes like protein biosynthesis. Aminoacylated nucleosides in tRNA represent the central transfer unit of amino acids in the biosynthesis of peptides. Consequently, their synthesis in a prebiotic context is of great significance for further elucidations regarding the origin of life. To verify the formation of these structures in complex mixtures of regio- and stereoisomers, reference structures and their synthesis are of fundamental importance. However, state-of-the-art methodologies for the synthesis of monomeric tRNA nucleoside derivatives frequently result in the production of regioisomeric mixtures or encounter challenges related to isomerization. In this context, a concise and comprehensive approach for the chemical synthesis of nucleosidic amino acid esters is presented. The three-step reaction sequence exploits the phenomenon of 2'-3'-transaminoacylation in nucleosides providing the desired compounds in high yields. This biomimetic approach is further expanded to the activation of hydroxy groups by application of sulfonic acid esters. This has the potential to facilitate extensive modification via substitution or cross-coupling reactions, enabling the stereo- and regio-controlled transformation of nucleosides into valuable target molecules or precursors in medicinal chemistry.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500395"},"PeriodicalIF":2.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109073","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
Recent Advances in the Photochemical Biology of Serotonin. 血清素光化学生物学研究进展。
IF 2.6 4区 生物学
ChemBioChem Pub Date : 2025-05-21 DOI: 10.1002/cbic.202500276
Claire E Nieder, Michael A Kienzler
{"title":"Recent Advances in the Photochemical Biology of Serotonin.","authors":"Claire E Nieder, Michael A Kienzler","doi":"10.1002/cbic.202500276","DOIUrl":"10.1002/cbic.202500276","url":null,"abstract":"<p><p>Serotonin (5-HT) is an endogenous neurotransmitter that plays a key role in cellular signaling. Its interactions with serotonin receptors (5-HTRs) and the serotonin transporter (SERT) influence processes as disparate as hunger, happiness, healing, and headaches. Over the last several decades, photochemical tools have been developed to observe, track, and modulate these serotonin-protein interactions. The tools tend to fit into one of four categories: photoswitches, photocages, photobiosensors, or photocross-linkers. This review examines the development and application of these photochemical tools for 5-HT, 5-HTRs, and SERT over the last ≈10 years, with an emphasis on the chemistry involved.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500276"},"PeriodicalIF":2.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118438","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
Nanobody-Based Light-Controllable Systems for Investigating Biology. 基于纳米体的光可控系统用于生物学研究。
IF 2.6 4区 生物学
ChemBioChem Pub Date : 2025-05-20 DOI: 10.1002/cbic.202500311
Donglian Wu, Simin Xia, Xi Chen
{"title":"Nanobody-Based Light-Controllable Systems for Investigating Biology.","authors":"Donglian Wu, Simin Xia, Xi Chen","doi":"10.1002/cbic.202500311","DOIUrl":"10.1002/cbic.202500311","url":null,"abstract":"<p><p>Nanobodies, the camelid-derived single-chain variable domain of heavy-chain-only antibodies, are compact in size and exhibit high binding affinity and specificity to their binding partners. As innovative antibody modalities, nanobodies have garnered significant attention in medicine and biological research. To achieve higher spatiotemporal precision, nanobody-based light-controlled systems-such as photobody, optobody, photoactivatable nanobody conjugate inducers of dimerization, and others-have been developed. These systems enable optical control of biological processes while leveraging the advantages of nanobodies as a binding moiety. This concept, summarizes nanobody-based photoregulated systems for investigating biology through light, highlights their advantages and potential limitations, and discusses future directions in this emerging research area.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500311"},"PeriodicalIF":2.6,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109072","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
A Polyproline Type II Peptidomimetic Disrupts a Grb2 SH3C Domain Protein-Protein Interaction Implicated in Breast Cancer. 聚脯氨酸II型拟肽破坏Grb2 SH3C结构域蛋白与乳腺癌相关的蛋白相互作用
IF 2.6 4区 生物学
ChemBioChem Pub Date : 2025-05-16 DOI: 10.1002/cbic.202500343
James Luccarelli, Philip C Simister, Andrew D Hamilton, Stephan M Feller, Sam Thompson
{"title":"A Polyproline Type II Peptidomimetic Disrupts a Grb2 SH3C Domain Protein-Protein Interaction Implicated in Breast Cancer.","authors":"James Luccarelli, Philip C Simister, Andrew D Hamilton, Stephan M Feller, Sam Thompson","doi":"10.1002/cbic.202500343","DOIUrl":"10.1002/cbic.202500343","url":null,"abstract":"<p><p>Given the essential role of protein-protein interactions (PPIs) in cellular signaling pathways, their selective modulation is of great therapeutic interest. Mimicry of secondary structural protein elements has emerged as a promising strategy, with various scaffolds reproducing recognition surfaces of α-helical and β-strand/sheet proteins. A critical PPI, controlling cell growth and proliferation in breast and other cancers, occurs between growth factor receptor-bound protein 2 (Grb2) and a polyproline II (PPII) helix embedded in Gab2. Herein, the first example of a general approach for nonpeptidic mimicry of extended PPII helices is presented and it is demonstrated that the scaffold may be functionalized to recapitulate the binding characteristics of crucial hydrophobic and cationic Gab2 hot-spot side-chains. The rationally designed peptidomimetic binds Grb2 at the same position as Gab2 (protein-observed nuclear magnetic resonance (NMR)) with affinities comparable to the native peptide sequence (surface plasmon resonance (SPR)). With the addition of a new PPII minimalist scaffold, these studies further validate the use of diverse secondary structure peptidomimetics in disrupting therapeutically relevant PPIs.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500343"},"PeriodicalIF":2.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075103","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
Changes in the Aqueous Solvent do not Impact the Internal Ring-Flip Dynamic of Fully Buried F52 in Protein GB1. 水溶液的变化不影响蛋白GB1中完全埋藏的F52的内环翻转动力学。
IF 2.6 4区 生物学
ChemBioChem Pub Date : 2025-05-16 DOI: 10.1002/cbic.202500183
Matthias Dreydoppel, Mikhail Achkinazi, Charlotte Krünholz, Paula L Jordan, Ulrich Weininger
{"title":"Changes in the Aqueous Solvent do not Impact the Internal Ring-Flip Dynamic of Fully Buried F52 in Protein GB1.","authors":"Matthias Dreydoppel, Mikhail Achkinazi, Charlotte Krünholz, Paula L Jordan, Ulrich Weininger","doi":"10.1002/cbic.202500183","DOIUrl":"10.1002/cbic.202500183","url":null,"abstract":"<p><p>Aromatic ring flips are a hallmark of protein dynamics. They are mediated by either transient \"breathing\" motions in which the protein expands into the solvent or by transient internal rearrangement of void spaces. Therefore, they are excellent reporters of such transient protein fluctuations. To decipher the extent to which ring-flip dynamics are governed by the protein itself or by the aqueous solvent around it, the ring flip of the fully buried aromatic side chain of F52 in protein B1 domain of immunoglobulin G binding protein G(GB1) with experimentally feasible altered buffer conditions by nuclear magnetic resonance relaxation dispersion experiments is studied. Herein, it is found that ring-flip rate constants remain the same in all studied cases. Therefore, the ring-flip dynamic in the interior of GB1 is independent from the solvent and only depends on the protein itself. In addition, this study shows that ring flips are comparable within different buffer conditions.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500183"},"PeriodicalIF":2.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075120","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
Photoinduced Ene-Reductase Catalysis via Electron Donor-Acceptor Complexes. 通过EDA配合物的光诱导酶还原酶催化。
IF 2.6 4区 生物学
ChemBioChem Pub Date : 2025-05-15 DOI: 10.1002/cbic.202500329
Shuang Liu, Runmiao Yang, Jian Xu
{"title":"Photoinduced Ene-Reductase Catalysis via Electron Donor-Acceptor Complexes.","authors":"Shuang Liu, Runmiao Yang, Jian Xu","doi":"10.1002/cbic.202500329","DOIUrl":"10.1002/cbic.202500329","url":null,"abstract":"<p><p>Flavin-dependent ene-reductases (EREDs) have emerged as powerful biocatalysts for the asymmetric reduction of various substrates. This review focuses on the recent advances in light-induced electron transfer and subsequent reduction reactions mediated by EREDs. Upon photoexcitation, the flavin cofactor transitions to an excited state, significantly enhancing its reduction potential. Mechanistic insights into how light activation alters the redox properties of EREDs are discussed, leading to more efficient catalysis. The review also highlights the broadened application scope of photoexcited EREDs in organic synthesis. Additionally, the challenges and future directions in optimizing these light-driven biocatalytic processes are explored. This overview provides a foundation for developing novel, light-controlled enzymatic systems with enhanced catalytic performance.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500329"},"PeriodicalIF":2.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075147","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
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