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First-in-Human Evaluation of [18F]FDOPA Produced by Organo-Photoredox Reactions. 对有机光氧化反应生成的[18F]FDOPA 进行首次人体评估。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-07-18 DOI: 10.1021/acs.bioconjchem.4c00252
Li Wang, Zhiyu Lv, Liping Yang, Xuedan Wu, Yan Zhu, Lin Liu, Yan Zhao, Zhanwen Huang, David A Nicewicz, Zhanhong Wu, Yue Chen, Zibo Li

Photoredox is a powerful synthetic tool in organic chemistry and has been widely used in various fields, including nuclear medicine and molecular imaging. In particular, acridinium-based organophotoredox radiolabeling has significantly impacted the production and discovery of positron emission tomography (PET) agents. Despite their extensive use in preclinical research, no PET agents synthesized by acridinium photoredox labeling have been tested in humans. [18F]FDOPA is clinically used for tumor diagnosis and the evaluation of neuropsychiatric disorders, but its application is limited by complex synthesis methods, the need for expensive modules, and/or the high cost of consumable materials/cassettes. In this report, we integrated a photoredox labeling unit with an automated module and produced [18F]FDOPA for human study. This research not only represents the first human study of a PET agent generated by acridinium-based organophotoredox reactions but also demonstrates the safety of this novel labeling method, serving as a milestone/reference for the clinical translation of other PET agents generated by this technique in the future.

光氧化是有机化学中一种强大的合成工具,已广泛应用于核医学和分子成像等多个领域。特别是基于吖啶的有机光氧放射标记对正电子发射断层扫描(PET)制剂的生产和发现产生了重大影响。尽管它们在临床前研究中得到了广泛应用,但还没有通过吖啶光氧标记合成的 PET 药剂在人体中进行过测试。[18F]FDOPA在临床上用于肿瘤诊断和神经精神疾病的评估,但其应用因复杂的合成方法、昂贵的模块需求和/或消耗材料/盒的高成本而受到限制。在本报告中,我们将光氧标记装置与自动化模块整合在一起,制备出了用于人体研究的[18F]FDOPA。这项研究不仅是对基于吖啶的有机光氧反应生成的 PET 制剂进行的首次人体研究,而且还证明了这种新型标记方法的安全性,为今后将这种技术生成的其他 PET 制剂应用于临床树立了里程碑/提供了参考。
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引用次数: 0
Tumor Metabolism: A New Field for the Treatment of Glioma. 肿瘤代谢:治疗胶质瘤的新领域。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-07-16 DOI: 10.1021/acs.bioconjchem.4c00287
Xiaoqian Chai, Yingjie Zhang, Wen Zhang, Kuanhan Feng, Yingyu Jiang, Anran Zhu, Xiaojin Chen, Liuqing Di, Ruoning Wang

The clinical treatment of glioma remains relatively immature. Commonly used clinical treatments for gliomas are surgery combined with chemotherapy and radiotherapy, but there is a problem of drug resistance. In addition, immunotherapy and targeted therapies also suffer from the problem of immune evasion. The advent of metabolic therapy holds immense potential for advancing more efficacious and tolerable therapies against this aggressive disease. Metabolic therapy alters the metabolic processes of tumor cells at the molecular level to inhibit tumor growth and spread, and lead to better outcomes for patients with glioma that are insensitive to conventional treatments. Moreover, compared with conventional therapy, it has less impact on normal cells, less toxicity and side effects, and higher safety. The objective of this review is to examine the changes in metabolic characteristics throughout the development of glioma, enumerate the current methodologies employed for studying tumor metabolism, and highlight the metabolic reprogramming pathways of glioma along with their potential molecular mechanisms. Importantly, it seeks to elucidate potential metabolic targets for glioblastoma (GBM) therapy and summarize effective combination treatment strategies based on various studies.

神经胶质瘤的临床治疗仍相对不成熟。临床上常用的胶质瘤治疗方法是手术结合化疗和放疗,但存在耐药性问题。此外,免疫疗法和靶向疗法也存在免疫逃避的问题。新陈代谢疗法的出现为针对这种侵袭性疾病开发更有效、更耐受的疗法带来了巨大的潜力。代谢疗法可在分子水平上改变肿瘤细胞的代谢过程,从而抑制肿瘤的生长和扩散,为对传统疗法不敏感的胶质瘤患者带来更好的治疗效果。此外,与传统疗法相比,它对正常细胞的影响更小,毒副作用更少,安全性更高。本综述旨在研究胶质瘤在整个发展过程中代谢特征的变化,列举目前用于研究肿瘤代谢的方法,并强调胶质瘤的代谢重编程途径及其潜在的分子机制。重要的是,本文试图阐明胶质母细胞瘤(GBM)治疗的潜在代谢靶点,并根据各种研究总结有效的联合治疗策略。
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引用次数: 0
Rational Design of Targeted Gold Nanoclusters with High Affinity to Integrin αvβ3 for Combination Cancer Therapy. 合理设计与整合素 αvβ3 高亲和力的靶向金纳米团簇,用于癌症联合疗法
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-07-15 DOI: 10.1021/acs.bioconjchem.4c00248
María Francisca Matus, Hannu Häkkinen

The unique attributes of targeted nano-drug delivery systems (TNDDSs) over conventional cancer therapies in suppressing off-target effects make them one of the most promising options for cancer treatment. There is evidence that the density of surface-conjugated ligands is a crucial factor in achieving the desired therapeutic efficacy of TNDDSs, but this is hardly manageable in conventional nanomaterials. In this context, ligand-protected gold nanoclusters (AuNCs) are excellent candidates for developing new TNDDSs with a unique control on their surface functionalities, thus helping to achieve enhanced delivery performance. Here, we study the interactions and binding free energies between ten different functionalized Au144(SR)60 (SR = thiolate ligand) nanoclusters and integrin αvβ3 using molecular dynamics simulations and the umbrella sampling method to obtain the optimal formulations. The AuNCs were functionalized with anticancer drugs (5-fluorouracil or signaling pathways inhibitors, such as capivasertib, linifanib, tanespimycin, and taselisib) and integrin-targeting peptides (RGD4C or QS13), and we identified the optimal mixed ligand layer to enhance their binding affinity to the cancer cell receptor. The results showed that changing the proportions of the same type of ligands on the surface of AuNCs led to differences of up to 38 kcal/mol in computed binding free energies. RGD4C as the targeting peptide resulted in greater affinity for αvβ3, and in most formulations studied, a higher amount of drug than peptide was needed. Polar and charged residues, such as Ser123, Asp150, Tyr178, Arg214, and Asp251 were found to play a significant role in AuNC binding. Our simulations also revealed that Mn2+ cations are crucial for stabilizing the αvβ3-AuNC complex. These findings demonstrate the potential of carefully designing the surface composition of TNDDSs to optimize their target affinity and specificity.

与传统癌症疗法相比,靶向纳米给药系统(TNDDSs)在抑制脱靶效应方面具有独特的特性,使其成为最有前途的癌症治疗方法之一。有证据表明,表面结合配体的密度是实现 TNDDSs 理想疗效的关键因素,但这在传统纳米材料中很难实现。在这种情况下,配体保护的金纳米团簇(AuNCs)是开发新型 TNDDSs 的绝佳候选材料,可对其表面功能进行独特的控制,从而有助于实现更高的递送性能。在此,我们利用分子动力学模拟和伞状取样法研究了十种不同功能化的 Au144(SR)60(SR = 硫代酸配体)纳米团簇与整合素 αvβ3 之间的相互作用和结合自由能,从而获得最佳配方。我们用抗癌药物(5-氟尿嘧啶或信号通路抑制剂,如capivasertib、linifanib、tanespimycin和taselisib)和整合素靶向肽(RGD4C或QS13)对AuNCs进行了功能化,并确定了最佳混合配体层,以增强它们与癌细胞受体的结合亲和力。结果表明,改变 AuNCs 表面同类配体的比例,可使计算出的结合自由能相差高达 38 kcal/mol。RGD4C 作为靶向肽对αvβ3 的亲和力更大,在研究的大多数制剂中,所需的药物量高于肽的量。研究发现,极性和带电残基(如 Ser123、Asp150、Tyr178、Arg214 和 Asp251)在 AuNC 的结合中发挥了重要作用。我们的模拟还发现,Mn2+ 阳离子对稳定 αvβ3-AuNC 复合物至关重要。这些研究结果表明,精心设计 TNDDSs 的表面组成可以优化其目标亲和力和特异性。
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引用次数: 0
Synthetic Amine Linkers for Efficient Sortagging. 用于高效分类的合成胺连接体。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-07-12 DOI: 10.1021/acs.bioconjchem.4c00143
Tetiana Bondarchuk, Diana Vaskiv, Elena Zhuravel, Oleh Shyshlyk, Yevhenii Hrynyshyn, Oleksandr Nedialko, Oleksandr Pokholenko, Alla Pohribna, Olga Kuchuk, Volodymyr Brovarets, Sergey Zozulya

Enzymatic site-specific bioconjugation techniques, in particular sortase-mediated ligation, are increasingly used to generate conjugated proteins for a wide array of applications. Extension of the utility and practicality of sortagging for diverse purposes is critically dependent on further improvement of the efficiency of sortagging reactions with a wider structural variety of substrates. We present a comprehensive comparative mass spectrometry screening study of synthetic nonpeptidic incoming amine nucleophile substrates of Staphylococcus aureus Sortase A enzyme. We have identified the optimal structural motifs among the chemically diverse set of 452 model primary and secondary amine-containing sortagging substrates, and we demonstrate the utility of representative amine linkers for efficient C-terminal biotinylation of nanobodies.

酶促位点特异性生物连接技术,特别是分选酶介导的连接技术,越来越多地用于生成连接蛋白,以满足广泛的应用需求。要扩大分选酶在各种用途中的作用和实用性,关键在于进一步提高分选酶与更多结构不同的底物发生反应的效率。我们对金黄色葡萄球菌分选酶 A 酶的合成非肽传入胺亲核底物进行了全面的质谱比较筛选研究。我们从化学性质多样的 452 种模型伯胺和仲胺亲核底物中找出了最佳结构基团,并证明了代表性胺连接体在纳米抗体 C 端生物素化方面的实用性。
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引用次数: 0
Lignin-Based Nanoparticles for Combination of Tumor Oxidative Stress Amplification and Reactive Oxygen Species Responsive Drug Release. 木质素基纳米颗粒结合肿瘤氧化应激放大和活性氧反应药物释放。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-07-11 DOI: 10.1021/acs.bioconjchem.4c00261
Ziwei Zhou, Jin Wang, Xin Xu, Zhuang Wang, Lingchen Mao, Shanhu Zhang, Huanhuan Zhang, Yuqiang Li, Qingsong Yu, Ni Jiang, Guan Zhang, Zhihua Gan, Zhenbo Ning

In this study, maleic anhydride-modified lignin (LG-M), a ROS-cleavable thioketal (TK) bond, and polyethylene glycol (PEG) were used to synthesize a lignin-based copolymer (LG-M(TK)-PEG). Doxorubicin (DOX) was attached to the ROS-cleavable bond in the LG-M(TK)-PEG for the preparation of the ROS-activatable DOX prodrug (LG-M(TK-DOX)-PEG). Nanoparticles (NPs) with a size of 125.7 ± 3.1 nm were prepared by using LG-M(TK-DOX)-PEG, and they exhibited enhanced uptake by cancer cells compared to free DOX. Notably, the presence of lignin in the nanoparticles could boost ROS production in breast cancer 4T1 cells while showing little effect on L929 normal cells. This selective effect facilitated the specific activation of the DOX prodrug in the tumor microenvironment, resulting in the superior tumor inhibitory effects and enhanced biosafety relative to free DOX. This work demonstrates the potential of the LG-M(TK-DOX)-PEG NPs as an efficient drug delivery system for cancer treatment.

本研究利用马来酸酐改性木质素(LG-M)、可被 ROS 分解的硫酮(TK)键和聚乙二醇(PEG)合成了一种木质素基共聚物(LG-M(TK)-PEG)。多柔比星(Doxorubicin,DOX)被连接到 LG-M(TK)-PEG中可被 ROS 分解的键上,以制备可被 ROS 激活的 DOX 原药(LG-M(TK-DOX)-PEG)。利用 LG-M(TK-DOX)-PEG制备的纳米颗粒(NPs)大小为 125.7 ± 3.1 nm,与游离 DOX 相比,它们在癌细胞中的吸收率更高。值得注意的是,纳米颗粒中木质素的存在可促进乳腺癌 4T1 细胞中 ROS 的产生,而对 L929 正常细胞影响甚微。这种选择性效应促进了 DOX 原药在肿瘤微环境中的特异性活化,从而产生了优于游离 DOX 的肿瘤抑制效果和生物安全性。这项工作证明了 LG-M(TK-DOX)-PEG NPs 作为一种高效的癌症治疗药物递送系统的潜力。
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引用次数: 0
Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions. 用于免疫疗法的靶向蛋白质降解(TPD):了解针对嵌合体驱动的泛素-蛋白酶体相互作用的蛋白质分解。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-07-11 DOI: 10.1021/acs.bioconjchem.4c00253
Rajamanikkam Kamaraj, Subhrojyoti Ghosh, Souvadra Das, Shinjini Sen, Priyanka Kumar, Madhurima Majumdar, Renesa Dasgupta, Sampurna Mukherjee, Shrimanti Das, Indrilla Ghose, Petr Pavek, Muruga Poopathi Raja Karuppiah, Anil A Chuturgoon, Krishnan Anand

Targeted protein degradation or TPD, is rapidly emerging as a treatment that utilizes small molecules to degrade proteins that cause diseases. TPD allows for the selective removal of disease-causing proteins, including proteasome-mediated degradation, lysosome-mediated degradation, and autophagy-mediated degradation. This approach has shown great promise in preclinical studies and is now being translated to treat numerous diseases, including neurodegenerative diseases, infectious diseases, and cancer. This review discusses the latest advances in TPD and its potential as a new chemical modality for immunotherapy, with a special focus on the innovative applications and cutting-edge research of PROTACs (Proteolysis TArgeting Chimeras) and their efficient translation from scientific discovery to technological achievements. Our review also addresses the significant obstacles and potential prospects in this domain, while also offering insights into the future of TPD for immunotherapeutic applications.

靶向蛋白质降解(TPD)作为一种利用小分子降解致病蛋白质的疗法正在迅速崛起。TPD 可以选择性地清除致病蛋白质,包括蛋白酶体介导的降解、溶酶体介导的降解和自噬介导的降解。这种方法在临床前研究中显示出巨大的前景,目前正被用于治疗多种疾病,包括神经退行性疾病、传染性疾病和癌症。这篇综述讨论了 TPD 的最新进展及其作为免疫疗法新化学模式的潜力,特别关注 PROTACs(蛋白质分解获取嵌合体)的创新应用和前沿研究,以及它们从科学发现到技术成果的高效转化。我们的综述还探讨了这一领域的重大障碍和潜在前景,同时还对 TPD 在免疫治疗应用中的未来发展提出了见解。
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引用次数: 0
Microwave-Assisted Synthesis of β-N-Aryl Glycoamphiphiles with Diverse Supramolecular Assemblies and Lectin Accessibility. 微波辅助合成β-N-芳基糖脂酰胺,具有多种超分子结构和连接蛋白可及性。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-07-10 DOI: 10.1021/acs.bioconjchem.4c00224
Aïcha Abdallah, Emilie Gillon, Patrice Rannou, Anne Imberty, Sami Halila

Glycoamphiphiles have attracted considerable interest in a broad range of application fields owing to their solution and bulk-state self-assembly abilities. Despite their importance, the straightforward synthesis of glycoamphiphiles consisting of a hydrophilic carbohydrate linked to a hydrophobic aglycone remains one of the major challenges in glycosciences. Here, a rapid, simple, and efficient synthetic access to chemically stable glycoamphiphiles at physiological pH, namely, N-(β-d-glycosyl)-2-alkylbenzamide, is reported. It leverages the nonreductive amination of unprotected carbohydrates with ortho-substituted aniline derivatives which could be readily obtained by reacting commercially available primary alkylamines with isatoic anhydride. This strategy avoids protection and deprotection of sugar hydroxyl groups and the use of reductive agents, which makes it advantageous in terms of atom and step economy. Moreover, in order to circumvent the cons of classical N-aryl glycosylation, we investigate the use of microwave as a heat source that provides fast, clean, and high-yield β-N-arylation of unprotected carbohydrates. Their self-assembly into water led to multiple morphologies of dynamic supramolecular glycoamphiphiles that were characterized to assess their ability to bind to lectins from pathogenic bacteria. Biophysical interactions probed by isothermal titration microcalorimetry revealed micromolar affinities for most of the synthesized glycoamphiphiles.

亲糖由于具有溶液和体态自组装能力,在广泛的应用领域引起了极大的兴趣。尽管它们非常重要,但直接合成由亲水性碳水化合物与疏水性苷元连接而成的亲糖仍是糖科学领域的主要挑战之一。本文报道了一种在生理 pH 值下快速、简单、高效合成化学性质稳定的糖脂酰胺的方法,即 N-(β-d-糖基)-2-烷基苯甲酰胺。它利用了未受保护的碳水化合物与正交取代的苯胺衍生物的非还原胺化反应,而苯胺衍生物可通过市售的伯烷基胺与异酸酐反应轻易获得。这种策略避免了对糖羟基的保护和脱保护,也避免了还原剂的使用,因此在原子和步骤经济方面具有优势。此外,为了规避经典 N-芳基糖基化的弊端,我们研究了利用微波作为热源,对未受保护的碳水化合物进行快速、清洁和高产率的β-N-芳基化。它们在水中的自组装产生了多种形态的动态超分子糖iphiles,我们对这些糖iphiles进行了表征,以评估它们与病原菌凝集素结合的能力。通过等温滴定微量热测定法探测的生物物理相互作用显示,大多数合成的糖iphiles 都具有微摩尔亲和力。
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引用次数: 0
AUNP-12 Near-Infrared Fluorescence Probes across NIR-I to NIR-II Enable In Vivo Detection of PD-1/PD-L1 Axis in the Tumor Microenvironment AUNP-12 近红外荧光探针跨越近红外-I 到近红外-II,可在体内检测肿瘤微环境中的 PD-1/PD-L1 轴。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-07-09 DOI: 10.1021/acs.bioconjchem.4c00266
Xinyu Zhang, Ping Wang, Guangyuan Shi, Chu Tang* and Huadan Xue*, 

The innovative PD-1/PD-L1 pathway strategy is gaining significant traction in cancer therapeutics. However, fluctuating response rates of 20–40% to PD-1/PD-L1 inhibitors, coupled with the risk of hyperprogression after immunotherapy, underscore the need for accurate patient selection and the identification of more beneficiaries. Molecular imaging, specifically near-infrared (NIR) fluorescence imaging, is a valuable alternative for real-time, noninvasive visualization of dynamic PD-L1 expression in vivo. This research introduces AUNP-12, a novel PD-L1-targeting peptide antagonist conjugated with Cy5.5 and CH1055 for first (NIR-I) and second near-infrared (NIR-II) imaging. These probes have proven to be effective in mapping PD-L1 expression across various mouse tumor models, offering insights into tumor-immune interactions. This study highlights the potential of AUNP-12-Cy5.5 and AUNP-12-CH1055 for guiding clinical immunotherapy through precise patient stratification and dynamic monitoring, supporting the shift toward molecular imaging for personalized cancer care.

创新的PD-1/PD-L1通路策略在癌症治疗中获得了极大的关注。然而,PD-1/PD-L1抑制剂的反应率仅为20%-40%,起伏不定,加上免疫疗法后存在过度进展的风险,因此需要准确选择患者并确定更多的受益者。分子成像,特别是近红外(NIR)荧光成像,是实时、无创地观察体内 PD-L1 动态表达的重要选择。这项研究介绍了一种新型 PD-L1 靶向肽拮抗剂 AUNP-12,它与 Cy5.5 和 CH1055 共轭,用于第一次(NIR-I)和第二次近红外(NIR-II)成像。事实证明,这些探针能有效绘制各种小鼠肿瘤模型的 PD-L1 表达图,从而深入了解肿瘤与免疫的相互作用。这项研究凸显了 AUNP-12-Cy5.5 和 AUNP-12-CH1055 通过对患者进行精确分层和动态监测来指导临床免疫疗法的潜力,支持了向分子成像治疗个性化癌症的转变。
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引用次数: 0
Rational Design of Cyanine-Based Fluorogenic Dimers to Reduce Nonspecific Interactions with Albumin and Lipid Bilayers: Application to Highly Sensitive Imaging of GPCRs in Living Cells. 减少与白蛋白和脂质双分子层的非特异性相互作用的氰基荧光二聚体的合理设计:应用于活细胞中 GPCR 的高灵敏度成像。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-07-09 DOI: 10.1021/acs.bioconjchem.4c00147
Yann Berthomé, Julie Gerber, Fabien Hanser, Stéphanie Riché, Nicolas Humbert, Christel Valencia, Pascal Villa, Julie Karpenko, Océane Florès, Dominique Bonnet

Fluorogenic dimers with polarity-sensitive folding are powerful probes for live-cell bioimaging. They switch on their fluorescence only after interacting with their targets, thus leading to a high signal-to-noise ratio in wash-free bioimaging. We previously reported the first near-infrared fluorogenic dimers derived from cyanine 5.5 dyes for the optical detection of G protein-coupled receptors. Owing to their hydrophobic character, these dimers are prone to form nonspecific interactions with proteins such as albumin and with the lipid bilayer of the cell membrane resulting in a residual background fluorescence in complex biological media. Herein, we report the rational design of new fluorogenic dimers derived from cyanine 5. By modulating the chemical structure of the cyanine units, we discovered that the two asymmetric cyanine 5.25 dyes were able to form intramolecular H-aggregates and self-quenched in aqueous media. Moreover, the resulting original dimeric probes enabled a significant reduction of the nonspecific interactions with bovine serum albumin and lipid bilayers compared with the first generation of cyanine 5.5 dimers. Finally, the optimized asymmetric fluorogenic dimer was grafted to carbetocin for the specific imaging of the oxytocin receptor under no-wash conditions directly in cell culture media, notably improving the signal-to-background ratio compared with the previous generation of cyanine 5.5 dimers.

具有极性敏感折叠的致荧光二聚体是用于活细胞生物成像的强大探针。它们只有在与目标相互作用后才会开启荧光,因此在免洗生物成像中具有很高的信噪比。我们曾报道过第一种由 5.5 号氰基染料衍生的近红外致荧光二聚体,用于光学检测 G 蛋白偶联受体。由于其疏水特性,这些二聚体容易与蛋白质(如白蛋白)和细胞膜脂质双分子层形成非特异性相互作用,导致在复杂的生物介质中产生残余背景荧光。在此,我们报告了从氰基 5 衍生出的新型致荧光二聚体的合理设计。通过调节氰基单元的化学结构,我们发现两种不对称的氰基 5.25 染料能够形成分子内 H-聚集体,并在水介质中自淬灭。此外,与第一代氰基 5.5 二聚体相比,由此产生的原始二聚体探针能够显著减少与牛血清白蛋白和脂质双分子层的非特异性相互作用。最后,将优化的不对称致荧光二聚体接枝到卡贝缩宫素上,在免洗条件下直接在细胞培养基中对催产素受体进行特异性成像,与上一代 5.5 氰二聚体相比,明显提高了信噪比。
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引用次数: 0
Permutational Encoding Strategy Accelerates HIT Validation from Single-Stranded DNA-Encoded Libraries 排列编码策略加速了单链 DNA 编码库的 HIT 验证。
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-07-04 DOI: 10.1021/acs.bioconjchem.4c00233
Sara Puglioli, Mosè Fabbri, Claudia Comacchio, Laura Alvigini, Roberto De Luca, Sebastian Oehler, Ettore Gilardoni, Gabriele Bassi, Samuele Cazzamalli, Dario Neri* and Nicholas Favalli*, 

DNA-Encoded Libraries (DELs) allow the parallel screening of millions of compounds for various applications, including de novo discovery or affinity maturation campaigns. However, library construction and HIT resynthesis can be cumbersome, especially when library members present an unknown stereochemistry. We introduce a permutational encoding strategy suitable for the construction of highly pure single-stranded single-pharmacophore DELs, designed to distinguish isomers at the sequencing level (e.g., stereoisomers, regio-isomers, and peptide sequences). This approach was validated by synthesizing a mock 921,600-member 4-amino-proline single-stranded DEL (“DEL1”). While screening DEL1 against different targets, high-throughput sequencing results showed selective enrichment of the most potent stereoisomers, with enrichment factors that outperform conventional encoding strategies. The versatility of our methodology was additionally validated by encoding 24 scaffolds derived from different permutations of the amino acid sequence of a previously described cyclic peptide targeting Fibroblast Activation Protein (FAP-2286). The resulting library (“DEL2”) was interrogated against human FAP, showing selective enrichment of five cyclic peptides. We observed a direct correlation between enrichment factors and on-DNA binding affinities. The presented encoding methodology accelerates drug discovery by facilitating library synthesis and streamlining HIT resynthesis while enhancing enrichment factors at the DEL sequencing level. This facilitates the identification of HIT candidates prior to medicinal chemistry and affinity maturation campaigns.

DNA 编码文库(DELs)可对数百万个化合物进行平行筛选,用于各种应用,包括全新发现或亲和力熟化活动。然而,文库构建和 HIT 再合成可能很麻烦,尤其是当文库成员的立体化学结构未知时。我们介绍了一种适用于构建高纯度单链单药食同源 DEL 的排列编码策略,其目的是在测序水平上区分异构体(如立体异构体、区域异构体和肽序列)。通过合成模拟的 921,600 个成员的 4-氨基脯氨酸单链 DEL("DEL1")验证了这种方法。在针对不同靶标筛选 DEL1 的过程中,高通量测序结果显示,我们选择性地富集了最有效的立体异构体,富集因子优于传统的编码策略。此外,我们还对 24 个支架进行了编码,这些支架来自之前描述的针对成纤维细胞活化蛋白(FAP-2286)的环状肽的氨基酸序列的不同排列,从而验证了我们的方法的多功能性。针对人类 FAP 对由此产生的文库("DEL2")进行了检测,结果显示五种环肽具有选择性富集。我们观察到富集因子与 DNA 结合亲和力之间存在直接关联。所介绍的编码方法促进了文库合成,简化了 HIT 的再合成,同时在 DEL 测序水平上提高了富集因子,从而加速了药物发现。这有助于在药物化学和亲和力成熟活动之前确定候选 HIT。
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引用次数: 0
期刊
Bioconjugate Chemistry Bioconjugate
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