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eSOMA-DM1, a Maytansinoid-Based Theranostic Small-Molecule Drug Conjugate for Neuroendocrine Tumors. eSOMA-DM1--一种治疗神经内分泌肿瘤的基于美坦素的治疗小分子药物共轭物。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-11-20 Epub Date: 2024-10-12 DOI: 10.1021/acs.bioconjchem.4c00413
Dylan Chapeau, Savanne Beekman, Amber Piet, Le Li, Corrina de Ridder, Debra Stuurman, Yann Seimbille

Background: 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. Methods: Synthesis of the DM1 moiety (4) involved a three-step synthetic route, followed by the conjugation to the cyclic peptide, N3-Py-DOTAGA-d-Phe-cyclo[Cys-Tyr-d-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. Results: 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. Conclusion: 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.

背景:传统化疗的主要挑战在于缺乏选择性和特异性,从而导致严重的副作用。使用小分子药物共轭物(SMDC)可将细胞毒性药物与靶向载体结合,确保特异性地输送到肿瘤部位。通过选择能与体生长抑素受体亚型 2(SSTR2)特异性结合的靶向载体,这一前景广阔的策略可应用于神经内分泌肿瘤(NET)。此外,在分子中加入双功能螯合物还能络合诊断性和治疗性放射性核素。因此,它有助于监测 SMDC 在体内的分布情况,并允许实施联合治疗。在我们的研究中,我们设计了 eSOMA-DM1,这是一种通过螯合连接体(N3-Py-DOTAGA)将 SSTR2 靶向 octreotate 肽和细胞毒剂 DM1 结合在一起的 SMDC。这种方法可将靶向载体和药物连接在相反的位点上,以避免不必要的立体阻碍效应。方法:DM1分子(4)的合成涉及三步合成路线,然后通过无铜点击反应与环肽N3-Py-DOTAGA-d-Phe-cyclo[Cys-Tyr-d-Trp-Lys-Thr-Cys]-Thr-OH连接,得到eSOMA-DM1。随后用[111In]InCl3进行标记,可获得较高的放射化学收率和纯度。在 SSTR2 转染的 U2OS 细胞中对 eSOMA-DM1 的结合、摄取和内化进行了体外评估。在携带 H69 肿瘤的小鼠体内进行了体内生物分布和荧光成像。结果:eSOMA-DM1 对 SSTR2 的 IC50 值与黄金标准 DOTA-TATE 相似。U2OS.SSTR2细胞对[111In]In-eSOMA-DM1的摄取量是[111In]In-DOTA-TATE的1.2倍。与[111In]In-DOTA-TATE相比,[111In]In-eSOMA-DM1在所有时间点对H69异种移植小鼠的肿瘤摄取率更高。长时间的血液循环导致[111In]In-eSOMA-DM1在肺部、皮肤和心脏等血管高度扩张的组织中蓄积增加。还观察到通过肾脏、肝脏和脾脏排泄的情况。结论:eSOMA-DM1 是一种针对 NET 开发的 SMDC,在体外显示出良好的特性。然而,使用[111In]In-eSOMA-DM1获得的体内结果表明,需要对其进行调整,以优化其分布。
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引用次数: 0
Recent Development of Chemigenetic Hybrid Voltage Indicators Enabled by Bioconjugation Chemistry. 利用生物共轭化学的化学遗传混合电压指示器的最新发展。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-11-20 Epub Date: 2024-10-30 DOI: 10.1021/acs.bioconjchem.4c00383
Shuzhang Liu, Peng Zou

Fluorescent voltage indicators enable the optical recording of electrophysiology across large cell populations with subcellular resolution; however, their application is often constrained by a limited photon budget. To address this limitation, advanced bioconjugation methods have been employed to site-specifically attach bright and photostable organic dyes to cell-specific protein scaffolds in live cells. The resulting chemigenetic hybrid voltage indicators enable sustained monitoring of voltage fluctuations with an exceptional signal-to-noise ratio, both in vitro and in vivo. This Viewpoint discusses recent advancements in the development of these indicators through bioconjugation chemistry.

荧光电压指示器能够以亚细胞分辨率光学记录大量细胞群的电生理学;然而,它们的应用往往受限于有限的光子预算。为了解决这一限制,我们采用了先进的生物共轭方法,在活细胞中将明亮、光稳定的有机染料特异性地连接到细胞特异性蛋白质支架上。由此产生的化学遗传混合电压指示器能在体外和体内以优异的信噪比持续监测电压波动。本视点讨论了通过生物共轭化学开发这些指示剂的最新进展。
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引用次数: 0
pH-Responsive Micelles Containing Quinine Functionalities Enhance Intracellular Gene Delivery and Expression. 含有奎宁功能的 pH 响应性胶束可增强细胞内基因的传递和表达。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-11-20 Epub Date: 2024-10-28 DOI: 10.1021/acs.bioconjchem.4c00326
Nicholas W Kreofsky, Punarbasu Roy, Theresa M Reineke

Quinine is a promising building block for creating polymer carriers for intracellular nucleic acid delivery. This is due to its ability to bind to genetic material through intercalation and electrostatic interactions and the balance of hydrophobicity and hydrophilicity dependent on the pH/charge state. Yet, studies utilizing cinchona alkaloid natural products in gene delivery are limited. Herein, we present the incorporation of a quinine functionalized monomer (Q) into block polymer architectures to form self-assembled micelles for highly efficient gene delivery. Q was incorporated into the core and/or the shell of the micelles to introduce the unique advantages of quinine to the system. We found that incorporation of Q into the core of the micelle resulted in acid-induced disassembly of the micelle and a boost in transfection efficiency by promoting endosomal escape. This effect was especially evident in the cancerous cell line, A549, which has a more acidic intracellular environment. Incorporation of Q into the shell of the micelles resulted in intercalative binding to the genetic payload as well as larger micelle-DNA complexes (micelleplexes) from the hydrophobicity of Q in the shell. These factors enable the micelleplexes to be more resistant to serum and have more persistent protein expression post-transfection. Overall, this study is the first to demonstrate the benefits of including quinine functionalities into self-assembled micelles for highly efficient gene delivery and presents a platform for inclusion of other natural products with similar properties into micellar systems.

奎宁是一种很有前景的聚合物载体,可用于细胞内核酸输送。这是因为奎宁能够通过插层作用和静电作用与遗传物质结合,而且疏水性和亲水性的平衡取决于 pH 值/电荷状态。然而,利用金鸡纳生物碱天然产物进行基因递送的研究还很有限。在此,我们介绍了将奎宁功能化单体(Q)掺入嵌段聚合物体系结构以形成自组装胶束从而实现高效基因递送的方法。Q被加入胶束的核心和/或外壳,为系统引入了奎宁的独特优势。我们发现,将 Q 加入胶束的核心会导致胶束在酸的诱导下解体,并通过促进内体逸出提高转染效率。这种效果在细胞内环境酸性更强的癌细胞系 A549 中尤为明显。将 Q 加入胶束的外壳后,可与基因载荷发生插层结合,同时由于 Q 在外壳中的疏水性,可形成较大的胶束-DNA 复合物(胶束复合物)。这些因素使胶束复合物更耐血清,转染后蛋白质表达更持久。总之,这项研究首次证明了在自组装胶束中加入奎宁功能以实现高效基因递送的好处,并为在胶束系统中加入具有类似性质的其他天然产品提供了一个平台。
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引用次数: 0
RPA-CRISPR-Cas-Mediated Dual Lateral Flow Assay for the Point-of-Care Testing of HPV16 and HPV18. RPA-CRISPR-Cas 介导的双侧流检测法用于 HPV16 和 HPV18 的床旁检测。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-11-20 Epub Date: 2024-10-15 DOI: 10.1021/acs.bioconjchem.4c00375
Kaini Zhang, Qingmei Li, Kun Wang, Qiaoli Zhang, Chengkun Ma, Guiwen Yang, Yanxia Xie, Michael G Mauk, Shanji Fu, Lei Chen

The incidence of cervical cancer caused by human papillomavirus (HPV) infection has increased in recent years. More than half of all cervical cancer cases are due to HPV16 and HPV18 infection, so HPV16 and HPV18 testing is essential to prevent cervical cancer. HPV testing is mainly carried out in hospitals, but it is subject to time and specialized medical facilities. On the other hand, home self-testing using simple diagnostics would present an attractive alternative due to privacy and flexibility with regard to time and place, provided sufficient sensitivity and specificity can be achieved. In this work, a dual lateral flow assay based on RPA-CRISPR-Cas12a/13a (named RC-LFA) for HPV detection was described. Taking advantage of the cleavage specificity of Cas12a and Cas13a, a CRISPR-Cas12a/Cas13a system was designed to detect HPV16 and HPV18. The lateral flow strip with two test lines was designed to suit the CRISPR-Cas12a/Cas13 system. RC-LFA achieves rapid and simultaneous detection of HPV16 and HPV18 with high specificity and sensitivity (10 copies/μL) in about 40 min from the extraction of nucleic acid to an instrument-free readout. RC-LFA is user-friendly and instrument-free, making it a promising method for HPV self-tests at home.

近年来,由人类乳头瘤病毒(HPV)感染引起的宫颈癌发病率有所上升。在所有宫颈癌病例中,有一半以上是由 HPV16 和 HPV18 感染所致,因此,HPV16 和 HPV18 检测对于预防宫颈癌至关重要。HPV 检测主要在医院进行,但受到时间和专业医疗设施的限制。另一方面,如果能达到足够的灵敏度和特异性,利用简单的诊断方法进行家庭自我检测将是一种有吸引力的替代方法,因为它具有隐私性和时间地点的灵活性。在这项工作中,描述了一种基于 RPA-CRISPR-Cas12a/13a 的双侧流检测法(命名为 RC-LFA),用于检测 HPV。利用 Cas12a 和 Cas13a 的裂解特异性,设计了一个 CRISPR-Cas12a/Cas13a 系统来检测 HPV16 和 HPV18。为适应 CRISPR-Cas12a/Cas13 系统,设计了带有两条检测线的侧流试纸。RC-LFA 可同时快速检测 HPV16 和 HPV18,特异性和灵敏度高(10 拷贝/μL),从提取核酸到无仪器读出约需 40 分钟。RC-LFA 操作简便,无需仪器,是一种很有前景的家庭 HPV 自我检测方法。
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引用次数: 0
Development of a Versatile Cancer Vaccine Format Targeting Antigen-Presenting Cells Using Proximity-Based Sortase A-Mediated Ligation of T-Cell Epitopes. 利用基于邻近性的分类酶 A 介导的 T 细胞表位连接技术,开发针对抗原呈递细胞的多功能癌症疫苗。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-11-20 Epub Date: 2024-11-07 DOI: 10.1021/acs.bioconjchem.4c00403
Aru Z Wang, Hendrik J Brink, Rianne G Bouma, Alsya J Affandi, Maarten K Nijen Twilhaar, Dijmphna A M Heijnen, Joelle van Elk, Janneke J Maaskant, Veronique A L Konijn, Joeke G C Stolwijk, Hakan Kalay, Katarina Olesek, Yvette van Kooyk, Johan M S van der Schoot, Arthur E H Bentlage, Ferenc A Scheeren, Martijn Verdoes, Gestur Vidarsson, Coenraad P Kuijl, Joke M M den Haan

Cancer vaccines are a promising strategy to increase tumor-specific immune responses in patients who do not adequately respond to checkpoint inhibitors. Cancer vaccines that contain patient-specific tumor antigens are most effective but also necessitate the production of patient-specific vaccines. This study aims to develop a versatile cancer vaccine format in which patient-specific tumor antigens can be site-specifically conjugated by a proximity-based Sortase A (SrtA)-mediated ligation (PBSL) approach to antibodies that specifically bind to antigen-presenting cells to stimulate immune responses. DEC205 and CD169 are both receptors expressed on antigen-presenting cells that can be targeted to deliver antigens and stimulate T-cell responses. We used the CRISPR/HDR platform to produce mouse heavy chain IgG2a antibodies with DEC205 or CD169 specificity containing an SrtA recognition motif followed by a SpyTag at the C-terminus. Using a recombinant protein of SrtA linked to SpyCatcher, we applied proximity-based SrtA-mediated ligation to ligate fluorescein isothiocyanate (FITC)-labeled or antigenic peptides to the antibodies. Ligated antibodies bound to DEC205-expressing dendritic cells or CD169-expressing macrophages both in vitro and in vivo. More importantly, immunization with DEC205- or CD169-specific Abs linked to T-cell epitopes efficiently stimulated T-cell responses in vivo. To conclude, we have developed a cancer vaccine format using PBSL that enables the rapid incorporation of tumor antigens and could potentially be implemented for the synthesis of personalized cancer vaccines.

癌症疫苗是一种很有前景的策略,可以提高对检查点抑制剂反应不充分的患者的肿瘤特异性免疫反应。含有患者特异性肿瘤抗原的癌症疫苗最为有效,但也需要生产患者特异性疫苗。本研究旨在开发一种多功能癌症疫苗形式,其中患者特异性肿瘤抗原可通过基于接近性的排序酶 A(SrtA)介导的连接(PBSL)方法与抗体特异性结合,从而特异性地结合到抗原递呈细胞上,刺激免疫反应。DEC205和CD169都是抗原递呈细胞上表达的受体,可以靶向递送抗原并刺激T细胞反应。我们利用 CRISPR/HDR 平台制备了具有 DEC205 或 CD169 特异性的小鼠重链 IgG2a 抗体,该抗体含有 SrtA 识别基序,C 端带有 SpyTag。利用与 SpyCatcher 连接的 SrtA 重组蛋白,我们采用基于 SrtA 介导的近距离连接技术将异硫氰酸荧光素(FITC)标记的肽或抗原肽连接到抗体上。连接后的抗体在体外和体内都能与表达 DEC205 的树突状细胞或表达 CD169 的巨噬细胞结合。更重要的是,用与 T 细胞表位相连的 DEC205 或 CD169 特异性抗体进行免疫,能有效激发体内的 T 细胞反应。总之,我们利用 PBSL 开发出了一种癌症疫苗形式,它能快速加入肿瘤抗原,有可能用于合成个性化癌症疫苗。
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引用次数: 0
Reactivity Profiling for High-Yielding Ynamine-Tagged Oligonucleotide Click Chemistry Bioconjugations. 高产率Ynamine标记寡核苷酸点击化学生物接合的反应性分析。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-11-20 Epub Date: 2024-10-10 DOI: 10.1021/acs.bioconjchem.4c00353
Frederik Peschke, Andrea Taladriz-Sender, Allan J B Watson, Glenn A Burley

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.

铜催化的叠氮-炔环加成反应(CuAAC)是制备生物共轭物的关键连接工具。尽管 CuAAC 广泛用于生产离散的 1,4-三唑产物,但由于需要使用铜催化剂,因此会对这些产物造成氧化损伤。在 CuAAC 反应中,Ynamines 是较好的反应基团,需要较低的 Cu 负载来生产 1,4-三唑产品。本研究揭示了一种确定形成寡脱氧核苷酸(ODN)生物共轭物最佳反应条件的策略。首先,通过对反应条件的调查发现,Cu 的比例和还原剂(即抗坏血酸钠或谷胱甘肽)的选择会影响反应动力学和生物共轭产物的降解率。其次,利用优化条件制备了多种 ODN 标记产品和 ODN 蛋白共轭物,并与传统的 CuAAC 和无铜叠氮-炔(3 + 2)环加成(SPAAC)进行了比较,结果表明在所有情况下,基于亚硝胺的例子都更快。本研究建立的反应优化平台为其在制备基于 CuAAC 的生物共轭物方面的广泛应用奠定了基础,该平台可在保持快速反应动力学的同时降低铜负载量。
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引用次数: 0
Bioorthogonal Chemistry: Enzyme Immune and Protein Capture for Enhanced LC-MS Bioanalysis. 生物正交化学:用于增强 LC-MS 生物分析的酶免疫和蛋白质捕获。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-11-20 Epub Date: 2024-10-29 DOI: 10.1021/acs.bioconjchem.4c00423
Xiaotong Wang, Duanmin Hu, Perry G Wang, Shuang Yang

Immunocapture liquid chromatography-mass spectrometry (IC-LC-MS) bioanalysis has become an indispensable technique across various scientific disciplines, ranging from drug discovery to clinical diagnostics. While traditional immunocapture techniques have proven to be effective, they often encounter limitations in sensitivity, specificity, and compatibility with MS analysis. Chemoenzymatic immunocapture and protein capture (IPC) offers a promising solution, combining the high specificity of antibodies or proteins with the versatility of enzymatic and chemical modifications. This Review explores the foundational principles of chemoenzymatic IPC and examines various modification strategies including bioorthogonal click-chemistry, enzymatic-tagging, and HaloTag/CLIP-tag. Recent advancements in chemoenzymatic IPC techniques have significantly expanded their applicability to a diverse range of biomolecules including small molecules, peptides, RNAs, and proteins. This Review focuses on improvements in analytical performance achieved through these innovative approaches. Moreover, we discuss the broad applications of chemoenzymatic immunocapture in drug discovery, clinical diagnostics, and environmental analysis and explore its potential for future advancements in bioanalysis. We propose a novel solid-phase chemoenzymatic IPC assay (SCEIA) that effectively utilizes bioorthogonal click chemistry and chemoenzymatic approaches for efficient IPC and target analyte release. In summary, chemoenzymatic IPC represents a transformative paradigm shift in IC-LC-MS bioanalysis. By overcoming the limitations of traditional IPC techniques, this approach paves the way for more robust, sensitive, and versatile analytical workflows.

免疫捕获液相色谱-质谱(IC-LC-MS)生物分析已成为从药物发现到临床诊断等各个科学领域不可或缺的技术。虽然传统的免疫捕获技术已被证明是有效的,但它们在灵敏度、特异性以及与质谱分析的兼容性方面往往存在局限性。化学酶免疫捕获和蛋白质捕获(IPC)将抗体或蛋白质的高特异性与酶和化学修饰的多功能性相结合,提供了一种很有前景的解决方案。本综述探讨了化学酶法 IPC 的基本原理,并研究了各种修饰策略,包括生物正交点击化学、酶标记和 HaloTag/CLIP-tag 等。化学酶法 IPC 技术的最新进展极大地扩展了其对小分子、肽、RNA 和蛋白质等各种生物大分子的适用性。本综述重点介绍通过这些创新方法提高分析性能的情况。此外,我们还讨论了化学酶免疫捕获在药物发现、临床诊断和环境分析中的广泛应用,并探讨了其在生物分析领域未来发展的潜力。我们提出了一种新型固相化学酶法 IPC 分析法(SCEIA),它有效地利用了生物正交点击化学和化学酶法来实现高效 IPC 和目标分析物的释放。总之,化学酶IPC代表了IC-LC-MS生物分析的变革性范式转变。这种方法克服了传统 IPC 技术的局限性,为更稳健、更灵敏、更多用途的分析工作流程铺平了道路。
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引用次数: 0
Drug Delivery Targeting Neuroinflammation to Treat Brain Diseases. 针对神经炎症的药物输送治疗脑部疾病。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-11-20 Epub Date: 2024-10-08 DOI: 10.1021/acs.bioconjchem.4c00414
Juntao Wang, Ruiqin Jia, Wubo Wan, Haijun Han, Guoying Wang, Zhen Li, Jia Li

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.

脑部炎症是多种脑部疾病的标志。炎症过程在这些疾病中的复杂作用表明,神经炎症可能是一个有价值的治疗靶点。虽然已经发现了几种很有前景的抗炎药物,但它们在脑部疾病中的临床应用往往因无法穿过血脑屏障(BBB)并在病变部位达到治疗有效浓度而受到阻碍。这一局限性凸显了人们对针对脑部炎症的有效 BBB 穿透性给药系统的迫切需求。本综述批判性地研究了过去五年来旨在缓解阿尔茨海默病和缺血性中风--全球两大致死致残原因--的脑部炎症的给药策略的最新进展。此外,我们还探讨了这一领域面临的主要挑战,并就针对神经炎症治疗脑部疾病的未来方向提出了见解。
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引用次数: 0
Correction to "Oriented Antibody Coupling to an Antifouling Polymer Using Glycan Remodeling for Biosensing by Particle Motion". 利用聚糖重塑将定向抗体耦合到防污聚合物上,通过粒子运动进行生物传感》的更正。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-11-20 Epub Date: 2024-10-28 DOI: 10.1021/acs.bioconjchem.4c00469
Maud D M E Linssen, Yu-Ting Lin, Sebastian A H van den Wildenberg, Marrit M E Tholen, Arthur M de Jong, Menno W J Prins
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引用次数: 0
Linker Chemistry and Connectivity Fine-Tune the Immune Response and Kinetic Solubility of Conjugated NOD2/TLR7 Agonists. 连接化学和连接性微调共轭 NOD2/TLR7 激动剂的免疫反应和动力学溶解度
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-11-20 Epub Date: 2024-10-10 DOI: 10.1021/acs.bioconjchem.4c00321
Špela Janež, Samo Guzelj, Žiga Jakopin

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.

人们对开发能够引起细胞免疫反应的新型免疫增效剂越来越感兴趣。我们利用两种先天性免疫受体--含核苷酸结合寡聚化结构域蛋白 2(NOD2)和 Toll 样受体 7(TLR7)--之间的协同交叉激活作用来应对这一挑战。在本文中,我们研究了一系列新型共轭 NOD2/TLR7 激动剂的结构-活性关系,这些激动剂含有多种柔性脂肪族、聚乙二醇基和三唑类连接体。我们的研究结果表明,共轭物在人类原代外周血单核细胞中具有强大的免疫增强特性,其特征是 Th1/Th17 极化细胞因子反应。重要的是,我们证明连接体的化学性质和连接部位都会影响这些共轭激动剂的免疫指纹和动力学溶解度。这些结果进一步揭示了 NOD2/TLR7 交叉激活的免疫刺激潜力,并为设计创新的免疫增强剂提供了启示。
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Bioconjugate Chemistry
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