Bioconjugate Chemistry最新文献

{"title":"eSOMA-DM1, a Maytansinoid-Based Theranostic Small-Molecule Drug Conjugate for Neuroendocrine Tumors","authors":"Dylan Chapeau,&nbsp;Savanne Beekman,&nbsp;Amber Piet,&nbsp;Le Li,&nbsp;Corrina de Ridder,&nbsp;Debra Stuurman and Yann Seimbille*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0041310.1021/acs.bioconjchem.4c00413","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00413https://doi.org/10.1021/acs.bioconjchem.4c00413","url":null,"abstract":"<p ><i>Background:</i> The main challenges of conventional chemotherapy lie in its lack of selectivity and specificity, leading to significant side effects. Using a small-molecule drug conjugate (SMDC) ensures specific delivery of a cytotoxic drug to the tumor site by coupling it to a targeting vector. This promising strategy can be applied to neuroendocrine tumors (NETs) by choosing a targeting vector that binds specifically to somatostatin receptor subtype 2 (SSTR2). Additionally, incorporation of a bifunctional chelate into the molecule enables complexation of both diagnostic and therapeutic radionuclides. Thus, it facilitates monitoring of the distribution of the SMDC in the body and allows for the implementation of combination therapy. In our study, we designed eSOMA-DM1, a SMDC combining the SSTR2-targeted octreotate peptide and the cytotoxic agent DM1 via a chelate-bridged linker (N₃–Py–DOTAGA). This approach warrants conjugation of the targeting vector and the drug at opposite sites to avoid undesired steric hindrance effects. <i>Methods:</i> Synthesis of the DM1 moiety (<b>4</b>) involved a three-step synthetic route, followed by the conjugation to the cyclic peptide, N₃–Py–DOTAGA-<span>d</span>-Phe-cyclo[Cys–Tyr-<span>d</span>-Trp–Lys–Thr–Cys]–Thr–OH, through a copper-free click reaction, resulting in eSOMA-DM1. Subsequent labeling with [¹¹¹In]InCl₃ gave a high radiochemical yield and purity. In vitro assessments of eSOMA-DM1 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. <i>Results:</i> eSOMA-DM1 exhibited an IC₅₀ value for SSTR2 similar to the gold standard DOTA-TATE. The uptake of [¹¹¹In]In–eSOMA-DM1 in U2OS.SSTR2 cells was 1.2-fold lower than that of [¹¹¹In]In–DOTA-TATE. Tumor uptake in H69-xenografted mice was higher for [¹¹¹In]In–eSOMA-DM1 at all-time points compared to [¹¹¹In]In–DOTA-TATE. Prolonged blood circulation led to increased accumulation of [¹¹¹In]In–eSOMA-DM1 in highly vascularized tissues, such as the lungs, skin, and heart. Excretion through the kidneys, liver, and spleen was also observed. <i>Conclusion:</i> eSOMA-DM1 is a SMDC developed for NET showing promising characteristics in vitro. However, the in vivo results obtained with [¹¹¹In]In–eSOMA-DM1 suggest the need for adjustments to optimize its distribution.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"35 11","pages":"1823–1834 1823–1834"},"PeriodicalIF":4.0,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linker Chemistry and Connectivity Fine-Tune the Immune Response and Kinetic Solubility of Conjugated NOD2/TLR7 Agonists","authors":"Špela Janež,&nbsp;Samo Guzelj and Žiga Jakopin*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0032110.1021/acs.bioconjchem.4c00321","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00321https://doi.org/10.1021/acs.bioconjchem.4c00321","url":null,"abstract":"<p >There is a growing interest in developing novel immune potentiators capable of eliciting a cellular immune response. We tackle this challenge by harnessing the synergistic cross-activation between two innate immune receptors─the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and Toll-like receptor 7 (TLR7). Herein, we investigate the structure–activity relationship of a series of novel conjugated NOD2/TLR7 agonists incorporating a variety of flexible aliphatic, poly(ethylene glycol)-based and triazole-featuring linkers. Our findings reveal potent immune-enhancing properties of conjugates in human primary peripheral blood mononuclear cells, characterized by a Th1/Th17 polarized cytokine response. Importantly, we demonstrate that both the chemistry of the linker and the site of linkage affect the immune fingerprint and the kinetic solubility of these conjugated agonists. These results shed further light on the immunostimulatory potential of NOD2/TLR7 cross-activation and provide insights for designing innovative immune potentiators.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"35 11","pages":"1723–1731 1723–1731"},"PeriodicalIF":4.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.4c00321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reactivity Profiling for High-Yielding Ynamine-Tagged Oligonucleotide Click Chemistry Bioconjugations","authors":"Frederik Peschke,&nbsp;Andrea Taladriz-Sender,&nbsp;Allan J.B. Watson* and Glenn A. Burley*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0035310.1021/acs.bioconjchem.4c00353","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00353https://doi.org/10.1021/acs.bioconjchem.4c00353","url":null,"abstract":"<p >The Cu-catalyzed azide–alkyne cycloaddition (CuAAC) reaction is a key ligation tool used to prepare bioconjugates. Despite the widespread utility of CuAAC to produce discrete 1,4-triazole products, the requirement of a Cu catalyst can result in oxidative damage to these products. Ynamines are superior reactive groups in CuAAC reactions and require lower Cu loadings to produce 1,4-triazole products. This study discloses a strategy to identify optimal reaction conditions for the formation of oligodeoxyribonucleotide (ODN) bioconjugates. First, the surveying of reaction conditions identified that the ratio of Cu to the choice of reductant (i.e., either sodium ascorbate or glutathione) influences the reaction kinetics and the rate of degradation of bioconjugate products. Second, optimized conditions were used to prepare a variety of ODN-tagged products and ODN-protein conjugates and compared to conventional CuAAC and Cu-free azide–alkyne (3 + 2)cycloadditions (SPAAC), with ynamine-based examples being faster in all cases. The reaction optimization platform established in this study provides the basis for its wider utility to prepare CuAAC-based bioconjugates with lower Cu loadings while maintaining fast reaction kinetics.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"35 11","pages":"1788–1796 1788–1796"},"PeriodicalIF":4.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.4c00353","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug Delivery Targeting Neuroinflammation to Treat Brain Diseases","authors":"Juntao Wang,&nbsp;Ruiqin Jia,&nbsp;Wubo Wan,&nbsp;Haijun Han,&nbsp;Guoying Wang,&nbsp;Zhen Li* and Jia Li*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0041410.1021/acs.bioconjchem.4c00414","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00414https://doi.org/10.1021/acs.bioconjchem.4c00414","url":null,"abstract":"<p >Inflammation within the brain is a hallmark of a wide range of brain diseases. The complex role of inflammatory processes in these conditions suggests that neuroinflammation could be a valuable therapeutic target. While several promising anti-inflammatory agents have been identified, their clinical application in brain diseases is often hampered by the inability to cross the blood-brain barrier (BBB) and reach therapeutically effective concentrations at the pathological sites. This limitation highlights the urgent need for effective BBB-penetrating drug delivery systems designed to target brain inflammation. This review critically examines the recent advances over the past five years in drug delivery strategies aimed at mitigating brain inflammation in Alzheimer’s disease and ischemic stroke─two of the leading causes of death and disability worldwide. Additionally, we address the key challenges in this field, offering insights into future directions for targeting neuroinflammation in the treatment of brain diseases.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"35 11","pages":"1687–1698 1687–1698"},"PeriodicalIF":4.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibitory Effects on RNA Binding and RNase H Induction Activity of Prodrug-Type Oligodeoxynucleotides Modified with a Galactosylated Self-Immolative Linker Cleavable by β-Galactosidase.","authors":"Kento Miyaji, Yoshiaki Masaki, Kohji Seio","doi":"10.1021/acs.bioconjchem.4c00376","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00376","url":null,"abstract":"<p><p>Prodrug-type oligonucleotides (prodrug-ONs) are a class of oligonucleotide designed for activation under specific intracellular conditions or external stimuli. Prodrug-ONs can be activated in the target tissues or cells, thereby reducing the risk of adverse effects. In this study, we synthesized prodrug-type oligodeoxynucleotides activated by β-galactosidase, an enzyme that is overexpressed in cancer and senescent cells. These oligodeoxynucleotides (ODNs) contain a modified thymidine conjugated with galactose via a self-immolative linker at the <i>O</i>4-position. UV-melting analysis revealed that the modifications decreased the melting temperature (<i>T</i>_m) compared with that of the unmodified ODN when hybridized with complementary RNA. Furthermore, cleavage of the glycosidic bond by β-galactosidase resulted in the spontaneous removal of the linker from the nucleobase moiety, generating unmodified ODNs. Additionally, the introduction of multiple modified thymidines into ODNs completely inhibited the RNase H-mediated cleavage of complementary RNA. These findings suggest the possibility of developing prodrug-ONs, which are specifically activated in cancer cells or senescent cells with high β-galactosidase expression.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive Review on Bubbles: Synthesis, Modification, Characterization and Biomedical Applications","authors":"Donald A. Fernandes*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0013710.1021/acs.bioconjchem.4c00137","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00137https://doi.org/10.1021/acs.bioconjchem.4c00137","url":null,"abstract":"<p >Accurate detection, treatment, and imaging of diseases are important for effective treatment outcomes in patients. In this regard, bubbles have gained much attention, due to their versatility. Bubbles usually 1 nm to 10 μm in size can be produced and loaded with a variety of lipids, polymers, proteins, and therapeutic and imaging agents. This review details the different production and loading methods for bubbles, for imaging and treatment of diseases/conditions such as cancer, tumor angiogenesis, thrombosis, and inflammation. Bubbles can also be used for perfusion measurements, important for diagnostic and therapeutic decision making in cardiac disease. The different factors important in the stability of bubbles and the different techniques for characterizing their physical and chemical properties are explained, for developing bubbles with advanced therapeutic and imaging features. Hence, the review provides important insights for researchers studying bubbles for biomedical applications.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"35 11","pages":"1639–1686 1639–1686"},"PeriodicalIF":4.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Bifunctional Chelating Agent for Tyrosine-Specific Radiolabeling of Peptides and Proteins.","authors":"Daiki Nakano, Hiroyuki Watanabe, Saito Kosuke, Masahiro Ono","doi":"10.1021/acs.bioconjchem.4c00363","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00363","url":null,"abstract":"<p><p>Site-specific radiolabeling is utilized for the development of antibody- or peptide-based radiotheranostic agents. Although tyrosine can be exploited as one of the target residues for site-specific radiolabeling of peptides and proteins, a tyrosine-specific radiolabeling method has not been established. In this study, we newly designed and synthesized a novel bifunctional chelating agent, TBD-DO3A, consisting of a triazabutadiene (TBD) scaffold and metal chelator, 1,4,7,10-tetraazacyclododecane 1,4,7-triacetic acid (DO3A). Conjugation of TBD-DO3A with Ac-Tyr-NHMe followed by ¹¹¹In-labeling afforded [¹¹¹In]In-Tyr-DO3A, which showed high-level stability in mouse plasma. Then, we selected the tyrosine-containing cyclic peptide c(RGDyK) as a model ligand and synthesized [¹¹¹In]In-RYD. [^111/natIn]In-RYD showed <i>in vitro</i> binding properties for integrin α_vβ₃ equivalent to those of [^111/natIn]In-RKD, a lysine residue-labeled control compound. In <i>in vivo</i> biodistribution and SPECT/CT imaging studies using U87MG/PC-3 tumor-bearing mice, [¹¹¹In]In-RYD and [¹¹¹In]In-RKD were selectively accumulated and facilitated U87MG tumor visualization at 24 h postinjection. These results indicate that TBD-DO3A has fundamental properties as a bifunctional chelator for tyrosine-specific radiolabeling of peptides and proteins.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linker and Conjugation Site Synergy in Antibody-Drug Conjugates: Impacts on Biological Activity.","authors":"Michihiko Aoyama, Minoru Tada, Hidetomo Yokoo, Takahito Ito, Takashi Misawa, Yosuke Demizu, Akiko Ishii-Watabe","doi":"10.1021/acs.bioconjchem.4c00348","DOIUrl":"10.1021/acs.bioconjchem.4c00348","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) produced using general conjugation methods yield heterogeneous products containing mixtures of species with different numbers of payloads per antibody (drug-antibody ratios) conjugated at multiple sites. This heterogeneity affects the stability, efficacy, and safety of ADCs. Thus, various site-specific conjugation methods have been developed to achieve homogeneity in ADCs. It was reported that linker structures and conjugation sites generally affected the characteristics of site-specific ADCs such as stability, efficacy, and safety. However, the combined effects of conjugation sites and linker structures on the physicochemical and biological characteristics of site-specific ADCs have remained unclear. In this study, we generated 30 homogeneous site-specific ADCs with a combination of six conjugation sites and five linker structures using THIOMAB technology and evaluated the characteristics of these homogeneous ADCs. We found that both conjugation sites and linker structures affected characteristics unique to ADCs (linker stability as well as target-dependent and target-independent cytotoxicity) in site-specific ADCs. Especially, conjugation to the constant regions of the light chain and the presence of polyethylene glycol structures in the linker are important for those ADC-specific characteristics. Interestingly, we also found that the effects of linker structures on the target-independent cytotoxicity of homogeneous ADCs at certain conjugation sites differed from those seen in conventional heterogeneous ADCs. Our results suggest that optimizing linker structures based on the conjugation site may be necessary for site-specific ADCs.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Novel Transasparaginase Activity of <i>Bacillus subtilis</i> (bTG) for Sequence-Specific Bioconjugation.","authors":"Marie Flamme, Raphael Göhring, Denise Zamarbide, Corentin Bon, Alexandra Vissières, Anne Basler, Daniela Miranda, Rainer Kneuer, Greg Mann","doi":"10.1021/acs.bioconjchem.4c00306","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00306","url":null,"abstract":"<p><p>The ability of <i>Bacillus subtilis</i> transglutaminase (bTG) to functionalize BSA has been investigated using peptide mapping experiments. Interestingly, the conjugation was not detected on a glutamine but on an asparagine residue. A sequence determination study was further performed, and a sequence of 10 amino acids for site-specific conjugation was identified. A monobody showing no native reactivity with the bTG enzyme was produced with the identified peptide sequences and successfully conjugated to various types of substrates in very high yields (>90%) with a 1/1/1.5 ratio of protein/amine/enzyme. Direct conjugation to the amino linker of a small interfering RNA (siRNA) was achieved in good yield, and no impact on the siRNA activity was observed following the conjugation. The identified sequences were further engineered in VHH and IgG scaffolds, and successful conjugation could also be observed with both small molecules and siRNA, confirming the potential of bTG for site-specific enzymatic bioconjugation.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Equimolar Cross-Coupling Using Reactive Coiled Coils for Covalent Protein Assemblies.","authors":"Hironori Takeuchi, Elee Shimshoni, Satish Gandhesiri, Andrei Loas, Bradley L Pentelute","doi":"10.1021/acs.bioconjchem.4c00327","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00327","url":null,"abstract":"<p><p>Biocompatible cross-coupling reactions enable the efficient covalent attachment of large biomolecules at near-stoichiometric ratios, ensuring the stability and integrity of the resulting products. We present an affinity-based peptide platform utilizing coiled coils containing reactive side chains for proximity-driven protein cross-coupling in the presence of a cross-linking agent. This platform supports both chemical synthesis and recombinant expression, using canonical amino acids to generate reactive affinity tags. Employing the E3/R3 coiled coil pair as a scaffold, we design four complementary coils with cysteine residues as cross-linking sites, achieving >90% conversion to covalent heterodimeric coupling products using 3,4-dibromomaleimide. Equimolar mixtures of proteins with reactive coils at their termini yield near-quantitative heterodimeric cross-coupling products. The strategic selection of complementary coiled coil pairs and cross-linking agents enables orthogonal assembly of macromolecules with diverse architectures. This method offers a versatile approach for creating covalent fusion proteins, enhancing their stability and functionality for applications in chemical biology, biotechnology, and medicine.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}