Bioconjugate Chemistry最新文献

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Antibody-Free Immunopeptide Nanoconjugates for Brain-Targeted Drug Delivery in Glioblastoma Multiforme 多形性胶质母细胞瘤脑靶向药物递送的无抗体免疫肽纳米偶联物。
IF 3.9 2区 化学
Bioconjugate Chemistry Pub Date : 2025-07-02 DOI: 10.1021/acs.bioconjchem.5c00168
Saurabh Sharma, , , David Lee, , , Surjendu Maity, , , Prabhjeet Singh, , , Jay Chadokiya, , , Neda Mohaghegh, , , Alireza Hassani, , , Hanjun Kim, , , Ankit Gangarade, , , Julia Y. Ljubimova, , , Amanda Kirane*, , and , Eggehard Holler*, 
{"title":"Antibody-Free Immunopeptide Nanoconjugates for Brain-Targeted Drug Delivery in Glioblastoma Multiforme","authors":"Saurabh Sharma,&nbsp;, ,&nbsp;David Lee,&nbsp;, ,&nbsp;Surjendu Maity,&nbsp;, ,&nbsp;Prabhjeet Singh,&nbsp;, ,&nbsp;Jay Chadokiya,&nbsp;, ,&nbsp;Neda Mohaghegh,&nbsp;, ,&nbsp;Alireza Hassani,&nbsp;, ,&nbsp;Hanjun Kim,&nbsp;, ,&nbsp;Ankit Gangarade,&nbsp;, ,&nbsp;Julia Y. Ljubimova,&nbsp;, ,&nbsp;Amanda Kirane*,&nbsp;, and ,&nbsp;Eggehard Holler*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00168","DOIUrl":"10.1021/acs.bioconjchem.5c00168","url":null,"abstract":"<p >Glioblastoma Multiforme (GBM) represents a significant clinical challenge among central nervous system tumors, with a dismal mean survival rate of less than 8 months, a statistic that has remained largely unchanged for decades (National Brain Society, 2022). The specialized intricate anatomical features of the brain, notably the blood-brain barrier (BBB), pose significant challenges to effective therapeutic interventions, limiting the potential reach of modern advancements in immunotherapy to impact these types of tumors. This study introduces an innovative, actively targeted immunotherapeutic nanoconjugate (P-12/AP-2/NCs) designed to serve as an immunotherapeutic agent capable of traversing the BBB via LRP-1 receptor-mediated transcytosis. P-12/AP-2/NCs exert their immune-modulating effects by inhibiting the PD-1/PD-L1 axis through a small-sized PD-L1/PD-L2 antagonist peptide, Aurigene NP-12 (P-12). P-12/AP-2/NCs are synthesized from completely biodegradable, functionalized high molecular weight β-poly(<span>l</span>-malic acid) (PMLA) polymer conjugated with P-12 and Angiopep-2 (AP-2) to yield P-12/AP-2/NCs. Evaluating nanoconjugates for BBB permeability and 3D tumor model efficacy using an in vitro BBB-Transwell spheroid-based model demonstrated successful crossing of the BBB and internalization in brain 3D tumor environments. In addition, the nanoconjugate mediated T cells' cytotoxicity on 3D tumor region death in a U87 GBM 3D spheroid model. AP-2/P-12/NCs are selectively inhibited in PD1/PDL1 interaction on T cells and the tumor site, increasing inflammatory cytokine secretion and T cell proliferation. In an in vivo murine brain environment, rhodamine fluorophore-labeled AP-2/P-12/NCs displayed significantly increased accumulation in the brain during 2–6 h time intervals postinjection with a prolonged bioavailability over unconjugated peptides. AP-2/P-12/NCs demonstrated a safety profile at both low and high doses based on major organ histopathology evaluations. Our findings introduce a novel, programmable nanoconjugate platform capable of penetrating the BBB for directed delivery of small peptides and significant immune environment modulation without utilizing antibodies, offering promise for treating challenging brain diseases such as glioblastoma multiforme and beyond.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 10","pages":"2132–2144"},"PeriodicalIF":3.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551427","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}
引用次数: 0
Tailoring the Methods of Conjugation and Characterization for a Replication-Competent, Live, Viral Vector 裁剪的方法偶联和表征的复制能力,活的,病毒载体。
IF 3.9 2区 化学
Bioconjugate Chemistry Pub Date : 2025-07-02 DOI: 10.1021/acs.bioconjchem.5c00060
Elise Ishida, Richard Dambra, Sally Ye, Steven Anderlot, Andrea Matter, Kaitlynn Graca, Yoo-Chun Kim, Travis Whitney, Yuecheng Xi, Leila Eslamizar, Ting Wang, Tom S. Chan, Sadia Abid, Leela Kurien, Mary Sanville, Aishwarya Bapat, Theophila Dusabamahoro, Andrey Konovalov, Amy Mikolaichik, Miguel A. Miranda-Roman, Audrey Brenot, Charles Wood, Birgit Fogal, Aaron M. Teitelbaum, Kelly Coble, Michael Franti, Kerstin Schaefer, Joseph Ashour* and Hamid Samareh Afsari*, 
{"title":"Tailoring the Methods of Conjugation and Characterization for a Replication-Competent, Live, Viral Vector","authors":"Elise Ishida,&nbsp;Richard Dambra,&nbsp;Sally Ye,&nbsp;Steven Anderlot,&nbsp;Andrea Matter,&nbsp;Kaitlynn Graca,&nbsp;Yoo-Chun Kim,&nbsp;Travis Whitney,&nbsp;Yuecheng Xi,&nbsp;Leila Eslamizar,&nbsp;Ting Wang,&nbsp;Tom S. Chan,&nbsp;Sadia Abid,&nbsp;Leela Kurien,&nbsp;Mary Sanville,&nbsp;Aishwarya Bapat,&nbsp;Theophila Dusabamahoro,&nbsp;Andrey Konovalov,&nbsp;Amy Mikolaichik,&nbsp;Miguel A. Miranda-Roman,&nbsp;Audrey Brenot,&nbsp;Charles Wood,&nbsp;Birgit Fogal,&nbsp;Aaron M. Teitelbaum,&nbsp;Kelly Coble,&nbsp;Michael Franti,&nbsp;Kerstin Schaefer,&nbsp;Joseph Ashour* and Hamid Samareh Afsari*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00060","DOIUrl":"10.1021/acs.bioconjchem.5c00060","url":null,"abstract":"<p >Optimized functionalization of virus particles can expand the toolbox available for the development of viral vector-based therapies. However, labeling of a large, complex, and biologically active particle introduces distinct technological challenges for subsequent purification and characterization steps. Moreover, the process of labeling and purification, and even the label itself, may have an unwanted impact on the particle’s biological activity. Herein, we present a comprehensive series of steps for conjugation, purification, and characterization that are adapted from traditional biologics (e.g., monoclonal antibodies) and apply them to the replication-competent rhabdovirus VSV-GP-GFP. By confirming purity and quantifying the average degree of labeling (DoL), we tailored the label/particle ratio to generate tool viruses suitable for downstream applications in nonclinical and clinical development. These methods will enhance the development of viral vector therapies and hasten their delivery to patients in need.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"1394–1408"},"PeriodicalIF":3.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551428","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}
引用次数: 0
Modulation of Membrane-Disruptive Activity of Melittin via N- and C-Terminal PEGylation Strategies 通过N端和c端聚乙二醇化策略调节蜂毒素的膜破坏活性。
IF 3.9 2区 化学
Bioconjugate Chemistry Pub Date : 2025-07-01 DOI: 10.1021/acs.bioconjchem.5c00123
Haonan Chen, Yuhang Dong*, Feng Shi* and Feng Li*, 
{"title":"Modulation of Membrane-Disruptive Activity of Melittin via N- and C-Terminal PEGylation Strategies","authors":"Haonan Chen,&nbsp;Yuhang Dong*,&nbsp;Feng Shi* and Feng Li*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00123","DOIUrl":"10.1021/acs.bioconjchem.5c00123","url":null,"abstract":"<p >Melittin has emerged as a promising therapeutic agent due to its potent antitumor and antimicrobial activities. However, the clinical translation of native Melittin is hindered by substantial challenges, including systemic toxicity and rapid proteolytic degradation, leading to suboptimal pharmacokinetic profiles. Therefore, structure–activity relationship-guided rational design strategies focusing on the molecular determinants of membrane penetration mechanisms are essential for optimizing Melittin’s therapeutic index. Herein, we synthesized a series of Melittin derivatives with varying PEG modification lengths and N- or C-terminus. Our evaluation revealed that N-terminal PEGylation substantially mitigated the cytotoxicity and hemolytic activity of Melittin while enhancing its proteolytic stability, where these beneficial properties exhibited progressive enhancement correlating with increasing PEG chain length. Conversely, C-terminal PEGylation demonstrated limited efficacy in modulating Melittin’s toxicity profile. Our findings elucidated that the membrane interaction mechanism of Melittin was predominantly mediated by its N-terminal helical domain, rather than the C-terminus, which initiated the cell membrane binding and subsequent pore formation, ultimately culminating in cell demise. This finding underscored the critical role of the N-terminus in the biological activity of Melittin. This study provided insight into the structure–activity relationship of PEGylated Melittin and established guidance for creating the next generation of peptide therapies.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"1438–1447"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537397","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}
引用次数: 0
Fluorescent PSMA-Targeted Radiotheranostic Compounds for Multiscale Imaging 用于多尺度成像的荧光psma靶向放射治疗化合物。
IF 3.9 2区 化学
Bioconjugate Chemistry Pub Date : 2025-06-27 DOI: 10.1021/acs.bioconjchem.5c00139
G. G. Simpson, J. M. Quintana, J. E. Carrothers, F. Jiang, S. A. Walker, C. Cho, R. Weissleder, M. A. Miller and T. S. C. Ng*, 
{"title":"Fluorescent PSMA-Targeted Radiotheranostic Compounds for Multiscale Imaging","authors":"G. G. Simpson,&nbsp;J. M. Quintana,&nbsp;J. E. Carrothers,&nbsp;F. Jiang,&nbsp;S. A. Walker,&nbsp;C. Cho,&nbsp;R. Weissleder,&nbsp;M. A. Miller and T. S. C. Ng*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00139","DOIUrl":"10.1021/acs.bioconjchem.5c00139","url":null,"abstract":"<p >Prostate-specific membrane antigen (PSMA) is a promising theranostic target. Different PSMA-targeting small molecule ligands have been FDA-approved or are in development, yet their biological fate at the single-cell level is often unknown. An improved understanding of the cellular distribution of these probes will confer insights into their microdosimetry and guide next-generation theranostic probe development. To enable detailed single-cell pharmacokinetics, it is desirable to have fluorescence affinity ligands that preserve the properties of the native agent. Building upon the structure of the FDA-approved PSMA-617, we synthesized a panel of fluorescent analogs and evaluated their in vitro and in vivo properties. We described a facile solid-phase-based synthesis and optimized the synthesis of the crucial urea pharmacophore. We identified two compounds, PSMA-Lys-DOTA-Cy680 (<b>3</b>) and PSMA-Lys-DOTA-AF647 (<b>4</b>), with similar PSMA binding affinities compared to the parent compound and robust optical imaging properties. Tissue and cellular biodistribution data from imaging can populate microdosimetric and systemic modeling to provide potential insights into future radiopharmaceutical therapy design.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"1448–1460"},"PeriodicalIF":3.9,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504141","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}
引用次数: 0
Impact of Conjugation Chemistry on the Pharmacokinetics of Peptide–Polymer Conjugates in a Model of Traumatic Brain Injury 偶联化学对外伤性脑损伤模型中肽-聚合物偶联物药代动力学的影响。
IF 3.9 2区 化学
Bioconjugate Chemistry Pub Date : 2025-06-27 DOI: 10.1021/acs.bioconjchem.5c00175
Jason Ren Wu, Akash Canjels, Rei Miyauchi and Ester J. Kwon*, 
{"title":"Impact of Conjugation Chemistry on the Pharmacokinetics of Peptide–Polymer Conjugates in a Model of Traumatic Brain Injury","authors":"Jason Ren Wu,&nbsp;Akash Canjels,&nbsp;Rei Miyauchi and Ester J. Kwon*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00175","DOIUrl":"10.1021/acs.bioconjchem.5c00175","url":null,"abstract":"<p >Traumatic brain injury (TBI) remains a leading cause of long-term disability and mortality; however, there are no effective therapies to mitigate secondary injury and long-term neurological impairments. After the initial mechanical insult, there is a secondary injury that leads to neuroinflammation and blood–brain barrier (BBB) disruption, both of which are linked to changes in the extracellular matrix (ECM). A short peptide sequence, CAQK (Cys-Ala-Gln-Lys), targets upregulated ECM proteoglycans after TBI and has exhibited therapeutic properties in preclinical TBI studies. However, like many peptides, CAQK has poor pharmacokinetics, with rapid systemic clearance limiting its therapeutic potential. To overcome these limitations, we investigated a peptide–polymer conjugate using a poly(ethylene glycol) (PEG) scaffold to improve the peptide pharmacokinetics of CAQK. We synthesized materials using two conjugation chemistries, maleimide–thiol Michael-type addition and dibenzocyclooctyne (DBCO)-azide strain-promoted azide–alkyne cycloaddition. The impact of linker selection on biodistribution and clearance was distinct. We first showed that conjugation of CAQK to PEG, irrespective of linkers, significantly extended the peptide's blood half-life by 90-fold and increased brain accumulation. In the analysis of off-target organs, we observed longer retention of DBCO conjugates in the liver, kidney, and spleen compared to maleimide conjugates. Given the high incidence of TBI in populations such as military personnel and athletes, we explored whether our long-circulating material could be given as a prophylaxis. We demonstrated the accumulation of 4.5%ID/g CAQK in the injured brain when the conjugate was delivered prophylactically 24 h before injury. Our work underscores the advantage of long-circulating peptide–polymer conjugates in the context of TBI and the impact of conjugation chemistry on pharmacokinetics.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"1483–1493"},"PeriodicalIF":3.9,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511263","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}
引用次数: 0
Near Infrared Light-Triggered Small Molecule Chemical Reactions in Biocompatible Systems 生物相容性系统中近红外光触发的小分子化学反应。
IF 3.9 2区 化学
Bioconjugate Chemistry Pub Date : 2025-06-27 DOI: 10.1021/acs.bioconjchem.5c00293
Jie Zhong, Yuhang Li, Xiaotong Li, Feng Liang, Ran Tao, Shan Qian* and Xinyuan Fan*, 
{"title":"Near Infrared Light-Triggered Small Molecule Chemical Reactions in Biocompatible Systems","authors":"Jie Zhong,&nbsp;Yuhang Li,&nbsp;Xiaotong Li,&nbsp;Feng Liang,&nbsp;Ran Tao,&nbsp;Shan Qian* and Xinyuan Fan*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00293","DOIUrl":"10.1021/acs.bioconjchem.5c00293","url":null,"abstract":"<p >Near-infrared (NIR) light, within the 700–1000 nm therapeutic optical window, offers deep tissue penetration, low photocytotoxicity, and minimal side effects, making it ideal for remote control of biocompatible reactions in vivo. This review explores recent advances in NIR-triggered reactions, focusing on direct and indirect activation strategies. Direct approaches utilize NIR-responsive protecting groups, while indirect methods employ upconversion materials and photocatalysis to overcome NIR’s energy limitations. These innovations expand noninvasive in vivo control capabilities. Applications include NIR-mediated drug delivery, biological molecule activation, and proximity labeling for protein interaction studies. Such reactions enable precise modulation of biological events under native conditions. The review highlights the potential of integrating advanced nanomaterials and optimizing indirect activation techniques to enhance reaction efficiency. It also emphasizes the requirement for interdisciplinary collaboration to refine NIR-responsive systems and facilitate clinical translation. By showcasing state-of-the-art NIR-controlled chemistry and identifying key areas for future research, this work aims to inspire advancements in biomedical research and therapeutics. Addressing the challenges of in vivo chemical control, this review positions NIR chemistry as a critical component in the evolution of biocompatible reaction methodologies.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"1362–1376"},"PeriodicalIF":3.9,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504142","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}
引用次数: 0
Chemo-Enzymatic Synthesis of Viscoelastic Pseudopeptidoglycan Networks 粘弹性假多肽聚糖网络的化学酶合成。
IF 3.9 2区 化学
Bioconjugate Chemistry Pub Date : 2025-06-24 DOI: 10.1021/acs.bioconjchem.5c00014
Philipp Loibner, David Bučak-Gasser, Katharina Schober, Tobias Steindorfer, Monika Brandtner, Tobias Dorn, Tanja Wrodnigg, Dmytro Neshchadin, Georg Gescheidt-Demner, Matej Bračič, Florian Lackner, Tamilselvan Mohan, Karin Stana Kleinschek and Rupert Kargl*, 
{"title":"Chemo-Enzymatic Synthesis of Viscoelastic Pseudopeptidoglycan Networks","authors":"Philipp Loibner,&nbsp;David Bučak-Gasser,&nbsp;Katharina Schober,&nbsp;Tobias Steindorfer,&nbsp;Monika Brandtner,&nbsp;Tobias Dorn,&nbsp;Tanja Wrodnigg,&nbsp;Dmytro Neshchadin,&nbsp;Georg Gescheidt-Demner,&nbsp;Matej Bračič,&nbsp;Florian Lackner,&nbsp;Tamilselvan Mohan,&nbsp;Karin Stana Kleinschek and Rupert Kargl*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00014","DOIUrl":"10.1021/acs.bioconjchem.5c00014","url":null,"abstract":"<p >Bacterial peptidoglycans (PGs) are essential targets for antibiotics and immune cells. Chemical methods to reproduce PGs semisynthetically are tedious and wasteful. In this work, we describe a new approach to form pseudo-PGs (PPGs) using the protease papain and custom-made peptides conjugated to a glycan. The kinetics of formation is monitored by rheology and <sup>1</sup>H NMR. Viscoelastic gels of controlled strength are formed, depending on the temperature and the number of peptide bridges between the glycan chains. We propose that the new method has a high impact on biomaterials research, since it could be used to deliver peptides, test antibiotic efficacy, or investigate human immune cell response.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 9","pages":"1933–1942"},"PeriodicalIF":3.9,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473408","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}
引用次数: 0
A Mild Protecting-Group Free Strategy for Neoglycoconjugate Synthesis 新糖缀合物的温和无保护基团合成策略。
IF 3.9 2区 化学
Bioconjugate Chemistry Pub Date : 2025-06-23 DOI: 10.1021/acs.bioconjchem.5c00138
Princey Raju, Chunhua Dong, Craig R. Garen, Michael T. Woodside and Christopher W. Cairo*, 
{"title":"A Mild Protecting-Group Free Strategy for Neoglycoconjugate Synthesis","authors":"Princey Raju,&nbsp;Chunhua Dong,&nbsp;Craig R. Garen,&nbsp;Michael T. Woodside and Christopher W. Cairo*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00138","DOIUrl":"10.1021/acs.bioconjchem.5c00138","url":null,"abstract":"<p >The synthesis of neoglycoconjugates has paved the way for the discovery of novel probes that mimic natural glycoconjugates and can provide designed research tools and therapeutics. In some cases, the target protein may not be amenable to harsh conditions; therefore, semisynthetic or chemical methods must be chosen with care. Here, we present a simple and modular chemoselective coupling strategy between an unprotected sugar and an <i>N</i>,<i>O</i>-disubstituted hydroxylamine under mild acidic conditions. This strategy removes any need for protecting groups on the glycan. The terminal alkene group of the conjugate serves as an effective handle to allow facile conjugation to the protein of interest via thiol–ene coupling (TEC), with proteins bearing a cysteine or free thiol to prepare neoglycoconjugates. We demonstrate that the strategy is compatible with both N- and O-linked glycans using protecting-group free strategies and optimize the TEC conditions using a variety of photocatalysts. Finally, we test the method on an aggregation-prone protein, α-synuclein. We envision that this strategy could allow the construction of complex glycoconjugates for biological testing using isolated glycans, or for generation of conjugates where the protein of interest is sensitive to harsh conditions.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"1461–1473"},"PeriodicalIF":3.9,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473407","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}
引用次数: 0
TfR1-Binding Peptide Conjugation Facilitates Robust and Specific siRNA Delivery to the Central Nervous System tfr1结合肽偶联促进强大和特异性siRNA传递到中枢神经系统。
IF 3.9 2区 化学
Bioconjugate Chemistry Pub Date : 2025-06-21 DOI: 10.1021/acs.bioconjchem.5c00225
Tiancheng Fu, Fushun Fan, Yingying Lin, Zhenxian Mo, Minhua Zhou, Xiaolan Ye, Xiong Cai, Zaijun Zhang, Changgeng Qian and Xinjian Liu*, 
{"title":"TfR1-Binding Peptide Conjugation Facilitates Robust and Specific siRNA Delivery to the Central Nervous System","authors":"Tiancheng Fu,&nbsp;Fushun Fan,&nbsp;Yingying Lin,&nbsp;Zhenxian Mo,&nbsp;Minhua Zhou,&nbsp;Xiaolan Ye,&nbsp;Xiong Cai,&nbsp;Zaijun Zhang,&nbsp;Changgeng Qian and Xinjian Liu*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00225","DOIUrl":"10.1021/acs.bioconjchem.5c00225","url":null,"abstract":"<p >Transferrin receptor 1 (TfR1) is a ubiquitously expressed receptor characterized by rapid internalization kinetics and efficient receptor recycling, making it an attractive target for drug delivery. Herein, we investigated the potential of TfR1-binding peptide-siRNA conjugates for central nervous system (CNS)-specific gene silencing. A panel of TfR1-binding peptides and conjugation linkers were synthesized to enable siRNA attachment and evaluate their gene-silencing effects. Conjugation with the hTfR No. 894 peptide achieved effective siRNA delivery both <i>in vitro</i> and <i>in vivo</i>. Compared to ribose 2’-<i>O</i>-hexadecyl (C16)-siRNA conjugates, the hTfR No. 894-siRNA conjugation (<b>POC2</b>) elicited favorable pharmacokinetic characteristics and robust and durable silencing of the target gene across CNS regions following local administration, with minimal impact on peripheral tissues. These findings support TfR1-binding peptide conjugation as a promising strategy for CNS-targeted siRNA delivery.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"1377–1383"},"PeriodicalIF":3.9,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339690","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}
引用次数: 0
Design and Evaluation of Stable Cysteine-Modified Monobody Scaffolds for Mirror-Image Synthesis 稳定半胱氨酸修饰单体镜像合成支架的设计与评价。
IF 3.9 2区 化学
Bioconjugate Chemistry Pub Date : 2025-06-21 DOI: 10.1021/acs.bioconjchem.5c00181
Naoya Iwamoto, Saya Ohno, Kensuke Nakamura, Toshinori Naito, Sayaka Miura, Shinsuke Inuki, Hiroaki Ohno, Gosuke Hayashi, Hiroshi Murakami and Shinya Oishi*, 
{"title":"Design and Evaluation of Stable Cysteine-Modified Monobody Scaffolds for Mirror-Image Synthesis","authors":"Naoya Iwamoto,&nbsp;Saya Ohno,&nbsp;Kensuke Nakamura,&nbsp;Toshinori Naito,&nbsp;Sayaka Miura,&nbsp;Shinsuke Inuki,&nbsp;Hiroaki Ohno,&nbsp;Gosuke Hayashi,&nbsp;Hiroshi Murakami and Shinya Oishi*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00181","DOIUrl":"10.1021/acs.bioconjchem.5c00181","url":null,"abstract":"<p >Mirror-image proteins (<span>d</span>-proteins) are promising therapeutic molecules with high biological stability and low immunogenicity. We recently developed a novel <span>d</span>-monobody scaffold variant with reduced immunogenicity. This variant incorporates two cysteine substitutions that enable the chemical synthesis of <span>d</span>-monobodies via native chemical ligation. In this study, the structure–activity relationship of monobody scaffold variants was investigated to identify more suitable positions for cysteine modifications. Several monobody variants with different cysteine substitution patterns and additional cysteine-selective modifications were designed and synthesized. Comprehensive functional analysis of the synthetic monobody derivatives led to the identification of a favorable monobody scaffold with potent target binding and high thermal stability. The optimized monobody scaffold with a cysteine cross-linker was used to develop <span>d</span>-monobody with additional functional groups.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"1504–1515"},"PeriodicalIF":3.9,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339689","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}
引用次数: 0
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