ChemBioChemPub Date : 2025-06-12DOI: 10.1002/cbic.202500108
Feodor Belov, Hannah Bork, Luise Hänel, Manideep V Kollipara, Matthias Höhne, Harald Gröger, Jan von Langermann
{"title":"Chemoenzymatic Route toward a De Novo Enantioselective Total Synthesis of (S)-Baclofen Based on Metal-Catalyzed Hydroformylation and Enzymatic Transamination.","authors":"Feodor Belov, Hannah Bork, Luise Hänel, Manideep V Kollipara, Matthias Höhne, Harald Gröger, Jan von Langermann","doi":"10.1002/cbic.202500108","DOIUrl":"10.1002/cbic.202500108","url":null,"abstract":"<p><p>This study explores the chemoenzymatic synthesis of (S)-baclofen, which involves a sequential combination of transition metal catalysis and biocatalysis. The synthesis approach starts from a readily accessible cinnamic acid ester that is converted using a rhodium-based hydroformylation catalyst toward the corresponding chiral aldehyde. This compound is subsequently converted via a transaminase-catalyzed reaction system that yields the desired β-chiral amino acid ester and the final free β-chiral amino acid (S)-baclofen after a simple hydrolysis reaction. This synthesis concept does provide high atom efficiency and does not require an additional chiral resolution step of a racemic product.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500108"},"PeriodicalIF":2.6,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281800","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 : 2025-06-11DOI: 10.1002/cbic.202500289
Dayan A, Ilic S, Akabayov B
{"title":"Characterization of DnaB–DnaG Interaction in M. tuberculosis Using Small-Angle X-ray Scattering-Based Dissociation Assay","authors":"Dayan A, Ilic S, Akabayov B","doi":"10.1002/cbic.202500289","DOIUrl":"10.1002/cbic.202500289","url":null,"abstract":"<p>The complex interactions between helicase and primase, two key components of the replisome involved in DNA replication in <i>Mycobacterium tuberculosis</i> are studied. Utilizing purified, complementary domains of these proteins, a surface plasmon resonance (SPR) analysis and a cross-linking assay to characterize their binding dynamics are employed. The SPR analysis reveals a binding dissociation constant of 0.21 ± 0.08 μM, and the cross-linking assay suggests the possible formation of a heterodimer species. Importantly, a small-angle X-ray scattering dissociation assay to study the dynamic interactions between the proteins in solution is utilized. The findings provide new opportunities for targeted therapeutic strategies aimed at DNA replication in <i>M. tuberculosis</i> by revealing the structural interplay between helicase and primase.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"26 14","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202500289","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264931","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}
{"title":"Chemoenzymatic Synthesis of 3-Halochromones via Oxidative α-Halogenation of Enaminones in TPGS-750-M Micelles","authors":"Chisanu Krongyut, Jakkarin Limwongyut, Nittaya Wiriya, Anyanee Kamkaew, Ailada Jantasin, Rung-Yi Lai","doi":"10.1002/cbic.202500277","DOIUrl":"10.1002/cbic.202500277","url":null,"abstract":"<p>Synthesis strategies of chromones have been widely investigated due to the abundance of chromone moiety in bioactive compounds and natural products. Of which, 3-halochromones are a versatile set of precursors to synthetically access valuable compounds with chromone frameworks. Generally, 3-halochromones are synthesized from <i>o</i>-hydroxy enaminones through oxidative α-halogenation, a process that often uses toxic and corrosive chemicals. Herein, an alternative strategy is presented for oxidative α-halogenation catalyzed by vanadium-dependent chloroperoxidase from <i>Curvularia inaequalis</i> (<i>Ci</i>VCPO) with H<sub>2</sub>O<sub>2</sub>/KX (X = Cl, Br, and I) in an aqueous medium. With a micellar system from a surfactant TPGS-750-M, substrate concentration can be increased to 50 mM without compromising the yield, thereby, significantly reducing the use of organic solvents. Substrate scope investigation reveals that bromination and chlorination processes prefer electron-donating substituents although moderate electron-withdrawing groups are tolerated (20 examples). Additionally, iodination processes can be performed under the optimized condition. However, slow conversion indicates that further optimization is needed. It is also found that iodination can occur without <i>Ci</i>VCPO, albeit at a lower conversion. Further investigation suggests that such a conversion took place via I<sub>2</sub> generated in situ. Overall, this chemoenzymatic method can offer an environmentally friendly approach to access a variety of 3-bromo or 3-chlorochromones.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"26 14","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264932","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 : 2025-06-10DOI: 10.1002/cbic.202500296
Lixin Yang, Zhipeng Hu, Tingting Zhou, Dan Wang, Jie Xu, Naiwen Zhang, Dongbo Tang, Yifang Han, Hai Qian, Wei Shi
{"title":"Rational Design and Bioactive Screening of Peptide Inhibitors Targeting Host-Pathogen Interactions in Severe Fever with Thrombocytopenia Syndrome Virus.","authors":"Lixin Yang, Zhipeng Hu, Tingting Zhou, Dan Wang, Jie Xu, Naiwen Zhang, Dongbo Tang, Yifang Han, Hai Qian, Wei Shi","doi":"10.1002/cbic.202500296","DOIUrl":"10.1002/cbic.202500296","url":null,"abstract":"<p><p>Severe fever with thrombocytopenia syndrome virus (SFTSV) poses a significant threat to public health, with limited therapeutic options available. This study focuses on the rational design and screening of peptide inhibitors targeting host-pathogen interactions, specifically between the viral Gn glycoprotein and key host cell receptors, DC-SIGN and NMMHC-IIA. By employing molecular dynamics simulations, alanine scanning, and peptide docking techniques, peptides were designed to disrupt these protein-protein interactions. Among the synthesized candidates, peptides II-1 and II-4 demonstrate potent inhibitory activity against SFTSV infection, with reduced TCID<sub>50</sub> values in cellular assays and displayed exceptional affinity (KD = 7.381 × 10<sup>-8</sup> M, 1.439 × 10<sup>-8</sup> M), These peptides also exhibit low cytotoxicity and hemolytic toxicity, highlighting their safety profile. Molecular dynamics simulations confirm strong binding affinities for these peptides, underpinned by stable hydrogen bonding interactions. This research provides a promising platform for developing peptide-based therapeutics targeting SFTSV, paving the way for further preclinical evaluation and clinical applications.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500296"},"PeriodicalIF":2.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256901","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 : 2025-06-10DOI: 10.1002/cbic.202500340
Gilbert B. Ampomah, Eldon R. Hard, Matthew R. Pratt
{"title":"α-Synuclein Sequences from Long-Lived Animals Display Generally Diminished Aggregation Compared to Shorter-Lived Animals Including Humans","authors":"Gilbert B. Ampomah, Eldon R. Hard, Matthew R. Pratt","doi":"10.1002/cbic.202500340","DOIUrl":"10.1002/cbic.202500340","url":null,"abstract":"<p>The overall process of protein aggregation from soluble species to amyloid fibrils is toxic to neurons and can propagate along neuronal connections in ways that potentially explain the pathological progression in most neurodegenerative diseases. One of these aggregation-prone proteins is α-synuclein (α-Syn), which forms insoluble protein deposits in Parkinson's disease and other synucleinopathies. The majority of cases of Parkinson's disease occur fairly late in life, and even early-onset variants of the disease caused by mutations to α-Syn occur toward the end of the lifespan for prehistoric man. This suggests a lack of evolutionary pressure to prevent protein aggregation in animals with similar or shorter lifespans. However, α-Syn is also found in animals with notably longer lifespans. Here, this study tests the aggregation propensity of α-Syn sequences from short- and longer-lived animals at a range of evolutionary distances from humans. This study finds that, in general, longer-lived animals display slower α-Syn aggregation kinetics and the formation of smaller and less uniform fibrils. Overall, data indicate that some evolutionary pressure may have existed for preventing α-Syn aggregation, but that pressure is lost in the more recent branch of shorter-lived animals containing humans.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"26 14","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264934","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 : 2025-06-10DOI: 10.1002/cbic.202500316
Dong Min Kang, Nataliia Lukianenko, Ja-Hyun Baik, Yun Kyung Kim, Sungsu Lim
{"title":"Pathological Disulfide Bond Crosslinking: Molecular Insights into Amyloidogenesis and Diseases Progression.","authors":"Dong Min Kang, Nataliia Lukianenko, Ja-Hyun Baik, Yun Kyung Kim, Sungsu Lim","doi":"10.1002/cbic.202500316","DOIUrl":"10.1002/cbic.202500316","url":null,"abstract":"<p><p>Amyloidogenesis is a complex process in which normally soluble proteins misfold and assemble into β-sheet-rich aggregates known as amyloid fibrils. This pathological process is implicated in a broad range of diseases, including neurodegenerative disorders and systemic amyloidosis. Recent studies indicate that disulfide-crosslinking plays a central role in promoting protein aggregation by stabilizing misfolded intermediates. This review highlights the cellular pathways leading to abnormal disulfide bond formation and examines their impact on disease progression. Additionally, a discussion is made on how disulfide-crosslinked oligomeric species resist degradation, overwhelm proteostasis systems, and serve as precursors for amyloid fibrils. By understanding the role of disulfide crosslinks in protein aggregation, insights into amyloid pathogenesis are gained and potential therapeutic targets for intervention are identified.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500316"},"PeriodicalIF":2.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264933","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 : 2025-06-06DOI: 10.1002/cbic.202500332
Dominik Homann, Lewis Thomas-Hargreaves, Pascal Püllmann
{"title":"Probing Unspecific Peroxygenases for Non-Natural Nitrene Chemistry.","authors":"Dominik Homann, Lewis Thomas-Hargreaves, Pascal Püllmann","doi":"10.1002/cbic.202500332","DOIUrl":"10.1002/cbic.202500332","url":null,"abstract":"<p><p>Unspecific peroxygenases (UPOs) perform challenging oxyfunctionalization chemistry with high catalytic efficiency and reaction stability. In this report, nitrene chemistry to the current repertoire of UPO chemistry is added, utilizing the inexpensive commodity chemical hydroxylamine as cosubstrate. 1,2,3,4-tetrahydronaphthalene is investigated as model substrate using a diverse panel of UPOs, reaching turnover numbers up to 745 and enantiomeric excess values up to 62%. Overall, the first account of UPO activity regarding non-natural nitrene activities is reported.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":" ","pages":"e2500332"},"PeriodicalIF":2.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232794","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 : 2025-06-05DOI: 10.1002/cbic.202500169
Albert Kakkis, Linzhongyi Sun, Zhijie Xie, Maya Qaddourah, Philip E. Dawson, Brittany B. Sanchez, Brandon J. Orzolek, Florence M. Brunel, Joseph R. Stock, Robert V. Kolakowski, Ilia Korboukh, Jens C. Leon
{"title":"Synthesis of Chemically Diverse siRNA-Lipid Conjugates Enabled by Reversible Adsorption to Solid Support (RASS)","authors":"Albert Kakkis, Linzhongyi Sun, Zhijie Xie, Maya Qaddourah, Philip E. Dawson, Brittany B. Sanchez, Brandon J. Orzolek, Florence M. Brunel, Joseph R. Stock, Robert V. Kolakowski, Ilia Korboukh, Jens C. Leon","doi":"10.1002/cbic.202500169","DOIUrl":"10.1002/cbic.202500169","url":null,"abstract":"<p>Small interfering RNAs (siRNAs) directly regulate gene expression and are, thus, attractive targets for clinical development to treat a variety of human diseases. While “naked” siRNAs are poor drug candidates, numerous chemical modifications of siRNAs have been developed to lower nuclease-sensitivity, increase cellular uptake, and enable cell-type-specific targeting. One class of modifications that has received attention is postsynthetic lipidation, as the pharmacokinetics of siRNA–lipid conjugates have been found to vary significantly based on the structure of the lipid moiety. While postsynthetic lipidation is a facile and effective means to render siRNAs more drug-like, most of these modifications occur in a single-step and in aqueous solution, engendering a limited chemical space. Herein, reversible adsorption of oligos onto a cationic solid support is demonstrated to facilitate postsynthetic, multistep modifications of single- and double-stranded siRNA in neat organic solvent to obtain siRNA–lipid conjugates with lipid moieties (e.g., long-chain alkyl thioethers, polyfluorinated biphenyl groups) that are challenging to incorporate using established postsynthetic lipidation procedures. RASS represents a rapid and convenient approach to generate siRNA–lipid conjugates encompassing a broad chemical space and ultimately a promising avenue to accelerate the discovery of potent siRNA therapeutics.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"26 13","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223813","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 : 2025-06-04DOI: 10.1002/cbic.202500321
Francesca D’Amico, Cami M. P. Talavera Ormeño, Shivanganie Poeran, Jimmy Akkermans, Rayman T. N. Tjokrodirijo, Bharath Sampadi, Peter van Veelen, Aysegul Sapmaz, Monique P. C. Mulder
{"title":"Advancing the Exploration of the Ubiquitin-like Protein FUBI with Synthetic Chemical Tools","authors":"Francesca D’Amico, Cami M. P. Talavera Ormeño, Shivanganie Poeran, Jimmy Akkermans, Rayman T. N. Tjokrodirijo, Bharath Sampadi, Peter van Veelen, Aysegul Sapmaz, Monique P. C. Mulder","doi":"10.1002/cbic.202500321","DOIUrl":"10.1002/cbic.202500321","url":null,"abstract":"<p>The Ubiquitin-like protein FUBI is encoded in humans by the FAU gene, whose down-regulation in prostate, ovarian and breast cancer is significantly associated with poor prognosis. Despite its implications in disease progression, the regulatory mechanisms orchestrated by FUBI remain elusive. To address this knowledge gap, a linear synthetic platform is developed to generate FUBI chemical tools, enabling the site-specific incorporation of unnatural building blocks and the introduction of fluorophores, tags, and reactive warheads. Using this platform, activity-based probes are created for FUBI conjugation and deconjugation enzymes, validating them in cell lysate-based assays and proteomics. Additionally, a triazole-linked Di-FUBI is synthesized to investigate FUBI chain modulators. Among the proteomics hits, IMPDH1 and the deubiquitinase UCHL3 are identified as novel Di-FUBI specific interactors. Further characterization revealed that Di-FUBI inhibits UCHL3 cleavage activity in a concentration-dependent manner, suggesting a novel regulatory interplay between UCHL3 and FUBI. Collectively, these tools demonstrate the versatility of the synthetic FUBI platform, advancing the characterization of FUBI-related enzymes in the ongoing efforts to decipher the complex code of ubiquitin-like signaling.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"26 14","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202500321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214466","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 : 2025-06-04DOI: 10.1002/cbic.202581101
Felix Veitl, Andreas Eichinger, Peter Mayrhofer, Markus R. Anneser, Mauricio Testanera, Kilian Rauscher, Matthias Lenz, Arne Skerra
{"title":"Front Cover: Engineering and Structural Elucidation of a Sac7d-Derived IgG Fc-Specific Affitin and Its Application for the Light-Controlled Affinity Purification of Antibodies (ChemBioChem 11/2025)","authors":"Felix Veitl, Andreas Eichinger, Peter Mayrhofer, Markus R. Anneser, Mauricio Testanera, Kilian Rauscher, Matthias Lenz, Arne Skerra","doi":"10.1002/cbic.202581101","DOIUrl":"https://doi.org/10.1002/cbic.202581101","url":null,"abstract":"<p>Antibodies (mAbs) are isolated in one step, under physiological conditions, via light-controlled affinity purification using an affitin derived from the Sac7d scaffold and the Azo-tag, thus overcoming limitations of conventional protein A chromatography and acid-triggered elution. X-ray crystallographic analysis and affinity measurements revealed complex formation of the affitin with Fc at the C<sub>H</sub>2/C<sub>H</sub>3 junction, similar to protein A/G and FnRn, which is remote from the binding site, hence allowing direct application of the purified mAb for biochemical or cell culture assays. More details can be found in article 2500102 by Arne Skerra and co-workers.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"26 11","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202581101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144206509","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}