ChemBioChemPub Date : 2025-05-21DOI: 10.1002/cbic.202500345
Laurence J Seabrook, Catherine R Livelo, Lauren V Albrecht
{"title":"Designing the Proteome with Chemical Tools: Degrons and Beyond.","authors":"Laurence J Seabrook, Catherine R Livelo, Lauren V Albrecht","doi":"10.1002/cbic.202500345","DOIUrl":"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, 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 toward 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":"e2500345"},"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}
ChemBioChemPub Date : 2025-05-21DOI: 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>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":"26 14","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202500395","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ChemBioChemPub Date : 2025-05-20DOI: 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>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":"26 14","pages":""},"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}
ChemBioChemPub Date : 2025-05-16DOI: 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>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 <i>α</i>–helical and <i>β</i>–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":"26 14","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202500343","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ChemBioChemPub Date : 2025-05-16DOI: 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>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":"26 13","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202500183","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ChemBioChemPub Date : 2025-05-15DOI: 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>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":"26 14","pages":""},"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}
{"title":"Amino Acid–Based Self-Assembled Supramolecular Structures: From Pathological Implications to Biomedical Applications","authors":"Pooja Sharma, Prabhjot Singh, Neelam, Nishima Wangoo","doi":"10.1002/cbic.202500228","DOIUrl":"10.1002/cbic.202500228","url":null,"abstract":"<p>Self-assembly is defined as a spontaneous ordering of molecules into distinct supramolecular structures similar to the naturally occurring biomolecules such as DNA, lipids, and proteins. Interestingly, this strategy has gained huge importance in recent decades, leading to substantial advancements in the biomedical field, including drug delivery, biosensing, tissue engineering, etc. The unique role of “FF” moiety in promoting self-aggregation in larger proteins is well established owing to its frequent occurrence in amyloids. This finding comes as a breakthrough in peptide nanotechnology research leading to the exploration of various peptide-based supramolecular structures demonstrating exceptional functional roles with futuristic applications. In this regard, since amino acids are the building blocks of peptides, the detailed investigation and discussion regarding their self-assembly behavior are expected to provide important insights into designing advanced functional materials from amino acids and peptides. This review provides a systematic overview of various latest findings on amino acid–based self-assembly and its pathological as well as functional role. The review also highlights the importance of emerging applications from self-assembled amino acid–based nanomaterials in the field of material science and biomedicine.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"26 13","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956062","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":"Photoactivatable Alkyne Tag for Photolabeling Biomolecules in Living Cells.","authors":"Yuki Umeda, Hao Zhu, Satoshi Yamaguchi, Sho Nakamura, Masato Takada, Shin Izuta, Akimitsu Okamoto","doi":"10.1002/cbic.202500190","DOIUrl":"10.1002/cbic.202500190","url":null,"abstract":"<p><p>Light-induced molecular imaging methods have attracted considerable attention owing to their potential for monitoring changes in the localization of intracellular molecules, which can provide valuable insights into the molecular mechanisms of living systems. In this article, a photoactivatable alkyne tag is developed by modifying an unstable intermediate of the alkyne-forming reaction with a photodegradable protecting group; the photodegradation triggers the conversion of the intermediate into a linear alkyne in an aqueous solution. The developed photoactivatable alkyne tag is incorporated into a cholesterol analog, introduced into living cells, and exposed to a biocompatible dose of 365 nm light. Subsequently, the cholesterol analog in light-irradiated cells is microscopically visualized through alkyne-specific biotinylation via copper-catalyzed azide-alkyne cycloaddition and biotin-specific labeling with fluorescence-labeled streptavidin. The obtained results indicate that the photoactivatable alkyne tag can be photoconverted into alkyne derivatives inside cells and applied to the light-induced intracellular imaging of biomolecules. This photoactivatable chemical tag can potentially expand the range of applications of light-induced molecular imaging of various biomolecules.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500190"},"PeriodicalIF":2.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075146","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}
ChemBioChemPub Date : 2025-05-13DOI: 10.1002/cbic.202500055
Dawei Ji, Rebecca L. Frkic, Javad Delyami, Joachim S. Larsen, Matthew A. Spence, Colin J. Jackson
{"title":"A Thermostable Bacterial Metallohydrolase that Degrades Organophosphate Plasticizers","authors":"Dawei Ji, Rebecca L. Frkic, Javad Delyami, Joachim S. Larsen, Matthew A. Spence, Colin J. Jackson","doi":"10.1002/cbic.202500055","DOIUrl":"10.1002/cbic.202500055","url":null,"abstract":"<p>A cyclase-phosphotriesterase (C-PTE) from <i>Ruegeria pomeroyi</i> DSS-3 has recently been identified for its capacity to detoxify several organophosphate compounds. However, several aspects of this enzyme remain unexplored, such as its activity with industrial organophosphates, its molecular structure, and its thermostability. In this work, the crystal structure of C-PTE is reported, which is solved to 2.3 Å resolution, providing insight into the enzyme's mechanism of action, revealing a binuclear Zn<sup>2+</sup> active site and distant similarity to other phosphotriesterases from the amidohydrolase superfamily. It is shown that C-PTE catalyzes the hydrolysis of the OP plasticizers triphenyl phosphate (TPhP) and tris(2-chloropropyl) phosphate (TCPP), albeit with low efficiency, but not the sterically bulkier tri-<i>o</i>-tolyl phosphate (ToTP). Finally, it is demonstrated that, even though <i>Ruegeria pomeroyi</i> DSS-3 is not a thermophile, C-PTE exhibits remarkable thermostability and retains structure up to 90 °C. Overall, these findings advance the understanding of C-PTE, suggesting that it is a good candidate for engineering owing to its thermostability and that it could contribute to bioremediation strategies to reduce the impact of pollution by industrial organophosphates.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"26 11","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202500055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957507","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}