Bioconjugate Chemistry最新文献

{"title":"Employing the SpyTag-SpyCatcher Reaction for the Modification of Supramolecular Polymers with Functional Proteins.","authors":"Fenna W B Craenmehr, Alexander Gräwe, Victor A Veenbrink, Riccardo Bellan, Maarten Merkx, Patricia Y W Dankers","doi":"10.1021/acs.bioconjchem.5c00046","DOIUrl":"10.1021/acs.bioconjchem.5c00046","url":null,"abstract":"<p><p>Supramolecular assemblies hold great potential as biomaterials for several biomedical applications. The modification of supramolecular biomaterials is needed to achieve controlled bioactive functions. Supramolecular ureidopyrimidinone (UPy) monomers have been shown to assemble into long supramolecular polymers that can be functionalized with bioactive peptides and visualized as UPy-fibers. So far, the introduction of biological functionality has been limited to small molecules and peptides. Here, we describe a general method based on SpyTag-SpyCatcher chemistry for conjugating full-length proteins with biologically relevant functions to μm-long UPy fibers via native peptide bond formation, yielding 100% conversion in a 5:95 mol % coassembly of UPy-SpyTag with UPy-glycinamide. The conjugation of monoclonal antibodies is performed using photo-cross-linkable protein G domains. We demonstrate intact fibers and colocalization of antibodies and UPy-fibers using biophysical and imaging methods and achieve recruitment of supramolecular assemblies to the surface of mammalian cells via the EGFR-specific antibody Cetuximab. The approach introduced here represents a robust and widely applicable postassembly modification method that shows promise in the functionalization of future biomaterials.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"1197-1207"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952197","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":"Developing and Characterizing the Tumor-Targeting Efficiency of an Anti-EphA2-CD11b Bispecific Antibody.","authors":"Peggy A Birikorang, Dominic M Menendez, Robert Edinger, Gary Kohanbash, W Barry Edwards","doi":"10.1021/acs.bioconjchem.5c00070","DOIUrl":"10.1021/acs.bioconjchem.5c00070","url":null,"abstract":"<p><p>Targeting molecules, such as antibodies and peptides, play a key role in the precise delivery of cytotoxic payloads to tumor sites by binding to specific tumor-associated antigens or other proteins within the tumor microenvironment. This investigation evaluates the potential therapeutic application of a bispecific antibody (BsAb), which simultaneously targets EphA2, a tumor-associated antigen, and CD11b, a protein expressed by tumor-associated macrophages and myeloid-derived suppressor cells (TAMCs). Recombinantly produced anti-EphA2-CD11b-BsAb was conjugated to a bifunctional chelator, NOTA-SCN, and then radiolabeled with copper-64 (⁶⁴Cu). The [⁶⁴Cu]Cu-NOTA-anti-EphA2-CD11b-BsAb radioimmunoconjugate was subsequently administered to HT1080-fibrosarcoma-bearing nude mice via tail vein injection. Positron Emission Tomography (PET) and ex vivo biodistribution analyses were performed to determine tumor uptake and pharmacokinetic localization. At 4, 24, and 48 h postinjection (p.i.), the percent injected dose per gram (%ID/g) of [⁶⁴Cu]Cu-NOTA-anti-EphA2-CD11b-BsAb in HT1080 xenografts were 5.35 ± 2.24, 4.44 ± 1.90, and 4.10 ± 0.60, respectively. There was high uptake in the liver as well as in CD11b-expressing organs, including the spleen, bone marrow, and lung. Binding in these CD11b-rich organs was significantly reduced by coadministering the dose with nonradiolabeled anti-CD11b-IgG and anti-EphA2-CD11b-BsAb, with a concurrent increase in tumor uptake compared to nonblocked mice (8.39 ± 1.37%ID/g for blocked and 4.44 ± 1.90%ID/g for nonblocked at 24 h p.i., <i>p</i> = 0.0175). Further optimization studies showed that at lower molar activity (3.7 MBq/nmol, 100 μCi/nmol), there were significantly higher tumor accumulations and reduced uptake in CD11b-expressing organs compared to higher molar activity (22.2 MBq/nmol, 600 μCi/nmol). Anti-EphA2-CD11b-BsAb is a functional targeting molecule and would require optimization through molar activity or blocking with nonradiolabeled antibody to maximize tumor targeting.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"1208-1217"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155223","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":"","authors":"Konstantin E. Katsuba,&nbsp;Lidia M. Zabegina,&nbsp;Daniil S. Plevako,&nbsp;Andrey A. Gurtovenko and Anastasia V. Malek*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144429454","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":"","authors":"Fenna W.B. Craenmehr,&nbsp;Alexander Gräwe,&nbsp;Victor A. Veenbrink,&nbsp;Riccardo Bellan,&nbsp;Maarten Merkx and Patricia Y.W. Dankers*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144355172","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":"","authors":"Yuxiang Cong,&nbsp;Xiaoxing Chen,&nbsp;Thulasiram Bathini,&nbsp;Gang Chen,&nbsp;Da Han,&nbsp;Yangen Huang* and Ruowen Wang*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144429453","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":"Targeting HER2 with DNA Aptamers for Efficient Anticancer Drug Delivery: A Combined Experimental and Computational Study.","authors":"Konstantin E Katsuba, Lidia M Zabegina, Daniil S Plevako, Andrey A Gurtovenko, Anastasia V Malek","doi":"10.1021/acs.bioconjchem.5c00022","DOIUrl":"10.1021/acs.bioconjchem.5c00022","url":null,"abstract":"<p><p>Targeted delivery of cytostatic drugs is a powerful approach to achieving tumor tissue selectivity, reducing systemic toxicity, and ultimately improving the efficacy of anticancer chemotherapy. Targeting can be achieved using a wide range of molecular ligands, with DNA aptamers being a promising representative. In this work, we employed flow cytometry, a AuNP-aptasensor, and atomic-scale computer modeling to assess the affinity of several DNA aptamers (Anti-HER2, HB5, Apt-6, HeA2_1, and HeA2_3) for human epidermal growth factor receptor 2 (HER2), which is known to be one of the factors that promote the growth of breast cancer cells. Flow cytometry showed that short aptamers (HeA2_1 and HeA2_3) had a higher affinity for HER2 on MDAMB453 cancer cells than longer aptamers (HB5, Apt-6). HER2-negative MDA-MB-231 cells served as the negative control. The HeA2_3 aptamer has a high average affinity (HeA2_3:23.6, HeA2_1:13.1, Apt-6:3.6; HB5:3.5; Anti-HER2:3.2) and a nearly Gaussian distribution across the cells, while HeA2_1 forms a fraction of cells with a relatively high fluorescence signal intensity (HeA2_1:11.6; HeA2_3:5.9; Apt-6:3.4; HB5:3.1; Anti-HER2:2.1). Most of the findings for cancer cells also hold for the HER2-positive small extracellular vesicles studied using the AuNP-aptasensor. Computer simulations confirmed that short aptamers are characterized by stronger binding to the extracellular domain of HER2. A detailed analysis of the free energy allowed us to show for the first time that tight binding to HER2 correlates with well-separated hot and cold spots on the protein surface. For the aptamers that meet these criteria (HeA2_1, HeA2_3, and Anti-HER2), favorable interactions with HER2 are driven by the local attraction of nucleotides to arginine and lysine residues of HER2 and possibly stabilized by intermolecular hydrogen bonds. For longer aptamers (Apt-6 and HB5), hot and cold spots on the HER2 surface overlap and the aptamers show much weaker binding. Overall, our findings show that binding of DNA aptamers to HER2 cannot be characterized merely by the dissociation equilibrium constant. A more sophisticated approach that combines experimental and computational methods allowed us to unlock the molecular mechanisms behind the aptamer-HER2 bindings. The results of our study also suggest that computer modeling has become a reliable and accurate tool for aptamer prescreening prior to laboratory experiments.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"1180-1196"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126220","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":"Design and Application of Conjugatable Small Molecule Toll-Like Receptor 4 Ligands.","authors":"Yutaro Mahara, Issa Fukuda, Ryuho Tanaka, Shin-Ya Oyama, Hiroyuki Shinchi, Yasuo Suda, Nikunj M Shukla, Michael Chan, Tomoko Hayashi, Howard B Cottam, Dennis A Carson, Masahiro Wakao","doi":"10.1021/acs.bioconjchem.5c00076","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00076","url":null,"abstract":"<p><p>We identified structurally distinct pyrimido[5,4-<i>b</i>]indole derivatives as toll-like receptor 4 (TLR4) ligands. Previous structure-activity relationship studies revealed that C8-aryl derivatives in pyrimido[5,4-<i>b</i>]indole, especially phenyl and 2-naphthyl compounds, are more potent in the activation of TLR4 signaling. Molecular modeling of these compounds indicated that C8-aryl groups are important for the interaction of the TLR4/myeloid differentiation factor-2 (MD-2) complex. Additionally, the modeling suggested that the N5 position in pyrimido[5,4-<i>b</i>]indole could be used as a further modification site to develop various drug conjugates. In this study, we examined whether the N5 position in pyrimido[5,4-<i>b</i>]indole can be used for conjugation without losing potency. Since tetraethylene glycol (TEG) derivatives at the N5 position were predicted to bind to TLR4/MD-2 complex using in silico molecular docking analysis, the compounds with the TEG group at the N5 position were synthesized and evaluated for immunostimulatory activity by human TLR4 reporter cell assay. As a result of fine-tuning of the C8 substitution groups, we found that TLR4 ligand (TLR4L) <b>10</b> with a 3-thienylethynyl group at the C8 position maintained TLR4 potency and demonstrated agonistic activity in primary murine bone marrow dendritic cells (mBMDC) and human TLR4 reporter HEK-Blue cells. TLR4L <b>10</b> was conjugated to sugar-immobilized gold nanoparticles (SGNPs) by introducing thioctic acid as a spacer into the TEG moiety. The obtained TLR4L-SGNPs <b>17</b> were taken up and showed agonistic activity in mBMDC. Thus, our designed TLR4L <b>10</b> and TLR4L-SGNP <b>17</b> are new candidates as immunomodulators for novel class adjuvant systems.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323842","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":"Transferrin Receptor-Targeted Aptamer-Drug Conjugate Overcomes Blood-Brain Barrier for Potent Glioblastoma Therapy.","authors":"Xinyue Zhao, Jiaxuan He, Yingda Chen, Jianpei Zheng, Xuefeng Li, Ting Fu, Sitao Xie, Xiangsheng Liu, Weihong Tan","doi":"10.1021/acs.bioconjchem.5c00137","DOIUrl":"10.1021/acs.bioconjchem.5c00137","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the leading primary malignant tumor in the central nervous system. Current clinical therapeutics for treating GBM patients yield limited benefits. However, the development of new therapeutic methods is hindered because the blood-brain barrier (BBB) restricts drug penetration. The transferrin receptor (TfR) is highly expressed by brain endothelial cells and GBM cells, and it is considered a promising target for GBM drug delivery. Here, we modularly constructed a TfR-targeted aptamerdrug conjugate (ApDC) by linking a TfR aptamer (HG1-9) and a highly potent anti-tubulin drug, monomethyl auristatin E (MMAE), to cross the BBB and deliver GBM treatment. The targeting and BBB transport abilities of the TfR-targeted ApDC (HG1-9-MMAE) for GBM were evaluated in cultured vascular endothelial bEnd.3 cells and human GBM U-87 MG Luc2 cells, together with an <i>in vitro</i> transwell BBB model. Potent antitumor effects of HG1-9-MMAE were demonstrated by <i>in vitro</i> cellular proliferation assays and <i>in vivo</i> tumor inhibition in both subcutaneous and orthotopic GBM models. Our findings indicated that ApDC could be an efficient drug delivery strategy to treat GBM.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"1288-1298"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954180","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":"","authors":"Susan Varghese,&nbsp;Merin K. Abraham,&nbsp;Geneva Indongo,&nbsp;Greeshma Rajeevan,&nbsp;Arathy B. K. Kala,&nbsp;Aishwarya Lekshman and Sony George*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00191","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144355171","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":"","authors":"Chengcheng Wang,&nbsp;Yapeng Wang,&nbsp;Yu Duan,&nbsp;Yuanzhen Dong,&nbsp;Haoju Hua,&nbsp;Huixin Cui,&nbsp;Shuaiyi Huang,&nbsp;Zongqing Huang,&nbsp;Jianguang Lu,&nbsp;Chunyong Ding*,&nbsp;Zhengyan Cai* and Jun Feng*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144355173","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}