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Characterisation of high throughput screening outputs for small molecule degrader discovery 用于发现小分子降解剂的高通量筛选结果的特征描述
IF 3.1 4区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-05-24 DOI: 10.1016/j.slasd.2024.100162
Lillie E. Bell , Catherine Bardelle , Martin J Packer , Johanna Kastl , Geoffrey A. Holdgate , Gareth Davies

Targeted protein degradation is an important mechanism carried out by the cellular machinery, one that is gaining momentum as an exploitable strategy for the development of drug-like compounds. Molecules which are able to induce proximity between elusive therapeutic targets of interest and E3 ligases which subsequently leads to proteasomal degradation of the target are beginning to decrease the percentage of the human proteome described as undruggable. Therefore, having the ability to screen for, and understand the mechanism of, such molecules is becoming an increasingly attractive scientific focus. We have established a number of cascade experiments including cell-based assays and orthogonal triage steps to provide annotation to the selectivity and mechanism of action for compounds identified as putative degraders from a primary high throughput screen against a high value oncology target. We will describe our current position, using PROTACs as proof-of-concept, on the analysis of these novel outputs and highlight challenges encountered.

靶向蛋白质降解是细胞机制的一种重要机制,作为一种可用于开发类药物的策略,这种机制的发展势头日益强劲。能够诱导难以捉摸的治疗靶点与 E3 连接酶接近,进而导致靶点蛋白酶体降解的分子,正在开始减少人类蛋白质组中被描述为不可药用的百分比。因此,有能力筛选并了解此类分子的作用机制正成为越来越有吸引力的科学焦点。我们已经建立了一系列级联实验,包括基于细胞的测定和正交分流步骤,以便为从针对高价值肿瘤靶点的初级高通量筛选中确定为推定降解剂的化合物提供选择性和作用机制注释。我们将以 PROTACs 作为概念验证,介绍我们目前在分析这些新产出方面的情况,并重点介绍我们遇到的挑战。
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引用次数: 0
Creating a more strategic small molecule biophysical hit characterization workflow 创建更具战略性的小分子生物物理命中表征工作流程。
IF 3.1 4区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-05-07 DOI: 10.1016/j.slasd.2024.100159
Christopher Fotsch , Debaleena Basu , Ryan Case , Qing Chen , Pratibha C. Koneru , Mei-Chu Lo , Rachel Ngo , Pooja Sharma , Amit Vaish , Xiang Yi , Stephan G. Zech , Peter Hodder

To confirm target engagement of hits from our high-throughput screening efforts, we ran biophysical assays on several hundreds of hits from 15 different high-throughput screening campaigns. Analyzing the biophysical assay results from these screening campaigns led us to conclude that we could be more strategic in our biophysical analysis of hits by first confirming activity in a thermal shift assay (TSA) and then confirming activity in either a surface plasmon resonance (SPR) assay or a temperature-related intensity change (TRIC) assay. To understand how this new workflow shapes the quality of the final hits, we compared TSA/SPR or TSA/TRIC confirmed and unconfirmed hits to one another using four measures of compound quality: quantitative estimate of drug-likeness (QED), Pan-Assay Interference Compounds (PAINS), promiscuity, and aqueous solubility. In general, we found that the biophysically confirmed hits performed better in the compound quality metrics than the unconfirmed hits, demonstrating that our workflow not only confirmed target engagement of the hits but also enriched for higher quality hits.

为了确认高通量筛选工作中筛选出的目标参与,我们对 15 次不同的高通量筛选活动中筛选出的数百个目标进行了生物物理测定。通过分析这些筛选活动的生物物理检测结果,我们得出结论:首先在热转移检测(TSA)中确认活性,然后在表面等离子体共振(SPR)检测或温度相关强度变化(TRIC)检测中确认活性,这样就能更有策略地对筛选结果进行生物物理分析。为了了解这一新的工作流程如何影响最终结果的质量,我们使用四种化合物质量衡量标准对 TSA/SPR 或 TSA/TRIC 确认结果和未确认结果进行了比较:药物相似性定量估计 (QED)、泛分析干扰化合物 (PAINS)、杂合性和水溶性。总的来说,我们发现生物物理确认的命中化合物在化合物质量指标中的表现优于未确认的命中化合物,这表明我们的工作流程不仅确认了命中化合物的靶点参与,而且还富集了更高质量的命中化合物。
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引用次数: 0
Enhancing scaffold-free spheroid models: 3D cell bioprinting method for metastatic HSC3–Oral squamous carcinoma cell line 增强无支架球体模型:转移性 HSC3-口腔鳞癌细胞系的三维细胞生物打印方法
IF 3.1 4区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-05-01 DOI: 10.1016/j.slasd.2024.100158
Taís Bacelar Sacramento de Araújo , Raphael Luís Rocha Nogueira , Leonardo de Oliveira Siquara da Rocha , Iasmin Nogueira Bastos , Rosane Borges Dias , Bruno Solano De Freitas Souza , Daniel William Lambert , Ricardo D. Coletta , Viviane Aline Oliveira Silva , Clarissa A. Gurgel Rocha

3D in vitro systems offer advantages over the shortcomings of two-dimensional models by simulating the morphological and functional features of in vivo-like environments, such as cell-cell and cell-extracellular matrix interactions, as well as the co-culture of different cell types. Nevertheless, these systems present technical challenges that limit their potential in cancer research requiring cell line- and culture-dependent standardization. This protocol details the use of a magnetic 3D bioprinting method and other associated techniques (cytotoxicity assay and histological analysis) using oral squamous cell carcinoma cell line, HSC3, which offer advantages compared to existing widely used approaches. This protocol is particularly timely, as it validates magnetic bioprinting as a method for the rapid deployment of 3D cultures as a tool for compound screening and development of heterotypic cultures such as co-culture of oral squamous cell carcinoma cells with cancer-associated fibroblasts (HSC3/CAFs).

三维体外系统通过模拟类似活体环境的形态和功能特征,如细胞-细胞和细胞-细胞外基质的相互作用,以及不同类型细胞的共培养,克服了二维模型的缺点。然而,这些系统在技术上存在挑战,限制了它们在癌症研究中的潜力,因为癌症研究需要依赖细胞系和培养的标准化。本方案详细介绍了利用口腔鳞状细胞癌细胞系 HSC3 使用磁性 3D 生物打印方法和其他相关技术(细胞毒性检测和组织学分析)的情况,与现有的广泛使用的方法相比,这种方法具有优势。该方案非常及时,因为它验证了磁性三维生物打印是一种快速部署三维培养物的方法,可作为化合物筛选和开发异型培养物(如口腔鳞状细胞癌细胞与癌症相关成纤维细胞(HSC3/CAFs)的共培养)的工具。
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引用次数: 0
POLARISED views and FRETting about probe modulation assays: Learning from High Throughput Screening 关于探针调制测定的 POLARISED 视图和 FRETting:从高通量筛选中学习
IF 3.1 4区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-04-18 DOI: 10.1016/j.slasd.2024.100156
Alice Lanne , Catherine Bardelle , Gareth Davies , Antonia Turberville , Hannah Semple , Rachel Moore , Geoffrey A. Holdgate

Fluorescent probe modulation assays are a widely used approach to monitor displacement or stabilisation of fluorescently labelled tool ligands by test compounds. These assays allow an optical read-out of probe-receptor binding and can be used to detect compounds that compete with the labelled ligand, either directly or indirectly. Probes for both orthosteric and allosteric sites are often employed. The method can also be used to identify test compounds that may stabilise the ternary complex, offering an opportunity to discover novel molecular glues. The utility of these fluorescence-based assays within high-throughput screening has been facilitated by the use of streptavidin labelled terbium as a donor and access to a range of different acceptor fluorophores. During 2023, the High-throughput Screening group at AstraZeneca carried out 8 high-throughput screens using these approaches. In this manuscript we will present the types of assays used, an overview of the timelines for assay development and screening, the application of orthogonal artefact methods to aid hit finding and the results of the screens in terms of hit rate and the number of compounds identified with IC50 values of better than 30 µM. Learning across the development, execution and analysis of these screens will be presented.

荧光探针调制测定是一种广泛使用的方法,用于监测荧光标记工具配体被测试化合物置换或稳定的情况。这些检测方法可对探针与受体的结合进行光学读数,并可用于检测与标记配体直接或间接竞争的化合物。通常采用的探针既可用于正交位点,也可用于异位位点。该方法还可用于鉴定可稳定三元复合物的测试化合物,为发现新型分子胶提供了机会。由于使用了链霉亲和素标记的铽作为供体,并可获得一系列不同的受体荧光团,这些基于荧光的检测方法在高通量筛选中的应用变得更加容易。2023 年期间,阿斯利康的高通量筛选小组利用这些方法进行了 8 次高通量筛选。在本手稿中,我们将介绍所使用的测定类型、测定开发和筛选的时间轴概述、应用正交伪影方法帮助寻找靶点的情况,以及从靶点率和鉴定出的 IC50 值优于 30 µM 的化合物数量来看筛选结果。此外,还将介绍在这些筛选的开发、执行和分析过程中学习到的知识。
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引用次数: 0
Aldehyde Dehydrogenase 2 (ALDH2): A novel sorafenib target in hepatocellular carcinoma unraveled by the proteome-wide cellular thermal shift assay 醛脱氢酶 2 (ALDH2):通过全蛋白质组细胞热转移测定揭示的肝癌索拉非尼新靶点
IF 3.1 4区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-04-01 DOI: 10.1016/j.slasd.2024.100154
Inês C. Ferreira , Estefania Torrejón , Bernardo Abecasis , Bruno M. Alexandre , Ricardo A. Gomes , Chris Verslype , Jos van Pelt , Ana Barbas , Daniel Simão , Tiago M. Bandeiras , Alessio Bortoluzzi , Sofia P. Rebelo

Sorafenib is a multikinase inhibitor indicated for first-line treatment of unresectable hepatocellular carcinoma. Despite its widespread use in the clinic, the existing knowledge of sorafenib mode-of-action remains incomplete. To build upon the current understanding, we used the Cellular Thermal Shift Assay (CETSA) coupled to Mass Spectrometry (CETSA-MS) to monitor compound binding to its target proteins in the cellular context on a proteome-wide scale. Among the potential sorafenib targets, we identified aldehyde dehydrogenase 2 (ALDH2), an enzyme that plays a major role in alcohol metabolism. We validated the interaction of sorafenib with ALDH2 by orthogonal methods using pure recombinant protein, proving that this interaction is not mediated by other cellular components. Moreover, we showed that sorafenib inhibits ALDH2 activity, supporting a functional role for this interaction. Finally, we were able to demonstrate that both ALDH2 protein expression and activity were reduced in sorafenib-resistant cells compared to the parental cell line. Overall, our study allowed the identification of ALDH2 as a novel sorafenib target and sheds light on its potential role in both hepatocellular carcinoma and sorafenib resistance condition.

索拉非尼是一种多激酶抑制剂,适用于不可切除肝细胞癌的一线治疗。尽管索拉非尼在临床上被广泛使用,但现有的关于索拉非尼作用模式的知识仍不完整。为了进一步了解索拉非尼的作用模式,我们使用了细胞热转移分析法(CETSA)和质谱分析法(CETSA-MS),在整个蛋白质组的范围内监测化合物与细胞内靶蛋白的结合情况。在索拉非尼的潜在靶标中,我们发现了醛脱氢酶 2(ALDH2),它是一种在酒精代谢中起重要作用的酶。我们使用纯重组蛋白,通过正交方法验证了索拉非尼与 ALDH2 的相互作用,证明这种相互作用不是由其他细胞成分介导的。此外,我们还发现索拉非尼抑制了 ALDH2 的活性,支持了这种相互作用的功能性作用。最后,我们还证明,与亲代细胞系相比,索拉非尼耐药细胞中的 ALDH2 蛋白表达量和活性都有所降低。总之,我们的研究将 ALDH2 鉴定为一种新型索拉非尼靶点,并揭示了它在肝癌和索拉非尼耐药情况下的潜在作用。
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引用次数: 0
Establishment, optimization and validation of a fluorescence polarization-based high-throughput screening assay targeting cathepsin L inhibitors 建立、优化和验证基于荧光偏振的 Cathepsin L 抑制剂高通量筛选试验。
IF 3.1 4区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-03-20 DOI: 10.1016/j.slasd.2024.100153
Wenwen Zhou , Baoqing You , Xiaomeng Zhao , Shuyi Si , Yan Li , Jing Zhang

Cathepsin L (CTSL), a lysosomal cysteine proteinase, is primarily dedicated to the metabolic turnover of intracellular proteins. It is involved in various physiological processes and contributes to pathological conditions such as viral infection, tumor invasion and metastasis, inflammatory status, atherosclerosis, renal disease, diabetes, bone diseases, and other ailments. The coronavirus disease 2019 (COVID-19), with its rapid global spread and significant mortality, has been a worldwide epidemic since the late 2019s. Notably, CTSL plays a role in the processing of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, providing a potential avenue to block coronavirus host cell entry and thereby inhibit SARS-CoV-2 infection in humans. In this study, we have developed a novel method using fluorescence polarization (FP) for screening CTSL inhibitors in a high-throughput format. The optimized assay demonstrated its appropriateness for high-throughput screening (HTS) with a Z-factor of 0.9 in a 96-well format. Additionally, the IC50 of the known inhibitor, Z-Phe-Tyr-CHO, was determined to be 188.50 ± 46.88 nM. Upon screening over 2000 small molecules, we identified, for the first time, the anti-CTSL properties of a benzothiazoles derivative named IMB 8015. This work presents a novel high-throughput approach and its application in discovering and evaluating CTSL inhibitors.

Cathepsin L(CTSL)是一种溶酶体半胱氨酸蛋白酶,主要负责细胞内蛋白质的代谢周转。它参与各种生理过程,并对病毒感染、肿瘤侵袭和转移、炎症状态、动脉粥样硬化、肾病、糖尿病、骨病等病理状态有一定的影响。冠状病毒病2019年最新注册送彩金(COVID-19)在全球迅速蔓延,死亡率高,自2019年最新注册送彩金末期以来一直是一种世界性流行病。值得注意的是,CTSL在严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2)尖峰蛋白的加工过程中发挥作用,为阻断冠状病毒宿主细胞进入从而抑制SARS-CoV-2感染人类提供了潜在途径。在这项研究中,我们开发了一种利用荧光偏振(FP)的新方法,以高通量形式筛选 CTSL 抑制剂。优化后的检测方法证明其适用于高通量筛选(HTS),在 96 孔格式中的 Z 因子为 0.9。此外,已知抑制剂 Z-Phe-Tyr-CHO 的 IC50 被确定为 188.50 ± 46.88 nM。在筛选了 2000 多种小分子后,我们首次发现了一种名为 IMB 8015 的苯并噻唑衍生物具有抗 CTSL 的特性。这项工作展示了一种新型高通量方法及其在发现和评估 CTSL 抑制剂中的应用。
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引用次数: 0
Outline and background for the EU-OS solubility prediction challenge 欧盟海洋观测系统溶解度预测挑战赛的概要和背景。
IF 3.1 4区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-03-20 DOI: 10.1016/j.slasd.2024.100155
Wenyu Wang , Jing Tang , Andrea Zaliani

In June 2022, EU-OS came to the decision to make public a solubility data set of 100+K compounds obtained from several of the EU-OS proprietary screening compound collections. Leveraging on the interest of SLAS for screening scientific development it was decided to launch a joint EUOS-SLAS competition within the chemoinformatics and machine learning (ML) communities. The competition was open to real world computation experts, for the best, most predictive, classification model of compound solubility. The aim of the competition was multiple: from a practical side, the winning model should then serve as a cornerstone for future solubility predictions having used the largest training set so far publicly available. From a higher project perspective, the intent was to focus the energies and experiences, even if professionally not precisely coming from Pharma R&D; to address the issue of how to predict compound solubility. Here we report how the competition was ideated and the practical aspects of conducting it within the Kaggle framework, leveraging of the versatility and the open-source nature of this data science platform. Consideration on results and challenges encountered have been also examined.

2022 年 6 月,EU-OS 决定公开从几个 EU-OS 专有筛选化合物库中获得的 100 多 K 个化合物的溶解度数据集。利用 SLAS 对筛选科学发展的兴趣,决定在化学信息学和机器学习 (ML) 社区内发起 EUOS-SLAS 联合竞赛。比赛面向现实世界中的计算专家,旨在选出最佳、最具预测性的化合物溶解度分类模型。比赛的目的是多方面的:从实用角度看,获胜模型应作为未来溶解度预测的基石,并使用迄今为止可公开获得的最大训练集。从更高的项目角度来看,目的是集中精力和经验(即使在专业上并非完全来自制药研发),解决如何预测化合物溶解度的问题。在此,我们将报告如何在 Kaggle 框架内构思比赛,以及利用这一数据科学平台的多功能性和开源性开展比赛的实际情况。此外,我们还探讨了比赛结果和遇到的挑战。
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引用次数: 0
High-throughput nephelometry methodology for qualitative determination of aqueous solubility of chemical libraries 用于定性测定化学文库水溶性的高通量尼泊金测定法
IF 3.1 4区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-03-06 DOI: 10.1016/j.slasd.2024.100149
Jose Brea , Maria J. Varela , Geert A. Daudey , Maria I. Loza

The purpose of the protocol reported in this work is the solubility profiling of large chemical libraries using nephelometry. This technique allows the qualitative classification of compounds as highly, moderately, or poorly water-soluble. The described methodology is not intended to yield quantitative solubility values of the studied compounds but can be used as a primary solubility assessment of large chemical libraries, to guide hit prioritization after High Throughput Screening (HTS) campaigns.

本研究中报告的方案旨在利用浊度测定法对大型化学库进行溶解度分析。这项技术可以将化合物定性地划分为高水溶性、中等水溶性和低水溶性。所描述的方法并不打算得出所研究化合物的定量溶解度值,但可用作大型化学文库的初级溶解度评估,以指导高通量筛选(HTS)活动后的筛选优先次序。
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引用次数: 0
Protocol for kinetic mode potassium channel assays on common plate readers and microscopes 在普通平板阅读器和显微镜上进行动力学模式钾通道检测的规程
IF 3.1 4区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-03-02 DOI: 10.1016/j.slasd.2024.100148
Emery Smith , Louise Dickson , Philip Pickford , Anna Rowland , Justin Shumate , Katherine Perez , Louis Scampavia , Derek Hernandez , Timothy P. Spicer

Fluorescence-based potassium channel assays are typically run on expensive, hard to obtain, fluorescence imaging kinetic plate readers that are uncommon in most laboratories. Here we describe the use of the Brilliant Thallium Snapshot assay to conduct an endpoint potassium channel assay, so that it can be used across multiple plate reader platforms that are more common in many labs. These methods will allow users to identify modulators of potassium channels. For this work, we have taken a kinetic mode Molecular Devices FLIPR based protocol and adapted it to be utilized on endpoint plate readers, such as the BMG Labtech PHERAstar, to identify activators of GIRK channels in CHO cells. We demonstrate that both plate readers are functionally competent at generating excellent Z’ values which makes them ideally suited to finding corollary hits from the Sigma LOPAC 1,280 screening collection. Importantly, this assay has also been validated using a high content reader, demonstrating the possibility of spatially resolving signals from individual cells within a mixed cell population. The compendium of these results shows the flexibility, accessibility and functionality of endpoint-compatible potassium channel assay readouts on more common plate readers.

基于荧光的钾通道测定通常在昂贵、难以获得的荧光成像动力学平板阅读器上运行,而这种平板阅读器在大多数实验室中并不常见。在此,我们将介绍如何使用亮铊快照检测法来进行终点钾通道检测,从而使其能够在许多实验室更为常见的多个平板阅读器平台上使用。这些方法将使用户能够识别钾通道的调节剂。在这项工作中,我们采用了基于动力学模式的 Molecular Devices FLIPR 方案,并对其进行了改良,使其可用于 BMG Labtech PHERAstar 等终点平板阅读器,以鉴定 CHO 细胞中 GIRK 通道的激活剂。我们证明,这两种平板阅读器在功能上都能产生出色的 Z'值,这使它们非常适合从 Sigma LOPAC 1,280 筛选集合中找到相关的命中物。重要的是,这种检测方法还通过高含量读板器进行了验证,证明了在混合细胞群中对单个细胞信号进行空间分辨的可能性。这些结果的汇总显示了在更常见的平板阅读器上进行终点兼容钾通道检测读数的灵活性、可及性和功能性。
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引用次数: 0
Establishment of a high-content imaging assay for tau aggregation in hiPSC-derived neurons differentiated from two protocols to routinely evaluate compounds and genetic perturbations 建立一种高浓度成像检测方法,用于检测由两种方案分化而来的 hiPSC 神经元中 tau 的聚集情况,以便对化合物和遗传扰动进行常规评估。
IF 3.1 4区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-03-01 DOI: 10.1016/j.slasd.2023.12.009
Lamiaa Bahnassawy , Nathalie Nicolaisen , Christopher Untucht , Benjamin Mielich-Süss , Lydia Reinhardt , Janina S. Ried , Martina P. Morawe , Daniela Geist , Anja Finck , Elke Käfer , Jürgen Korffmann , Matthew Townsend , Brinda Ravikumar , Viktor Lakics , Miroslav Cik , Peter Reinhardt

Aberrant protein aggregation is a pathological cellular hallmark of many neurodegenerative diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), where the tau protein is aggregating, forming neurofibrillary tangles (NFTs), and propagating from neuron to neuron. These processes have been linked to disease progression and a decline in cognitive function. Various therapeutic approaches aim at the prevention or reduction of tau aggregates in neurons. Human induced pluripotent stem cells (hiPSCs) are a very valuable tool in neuroscience discovery, as they offer access to potentially unlimited amounts of cell types that are affected in disease, including cortical neurons, for in vitro studies. We have generated an in vitro model for tau aggregation that uses hiPSC – derived neurons expressing an aggregation prone, fluorescently tagged version of the human tau protein after lentiviral transduction. Upon addition of tau seeds in the form of recombinant sonicated paired helical filaments (sPHFs), the neurons show robust, disease-like aggregation of the tau protein. The model was developed as a plate-based high content screening assay coupled with an image analysis algorithm to evaluate the impact of small molecules or genetic perturbations on tau. We show that the assay can be used to evaluate small molecules or screen targeted compound libraries. Using siRNA-based gene knockdown, genes of interest can be evaluated, and we could show that a targeted gene library can be screened, by screening nearly 100 deubiquitinating enzymes (DUBs) in that assay. The assay uses an imaging-based readout, a relatively short timeline, quantifies the extent of tau aggregation, and also allows the assessment of cell viability. Furthermore, it can be easily adapted to different hiPSC lines or neuronal subtypes. Taken together, this complex and highly relevant approach can be routinely applied on a weekly basis in the screening funnels of several projects and generates data with a turnaround time of approximately five weeks.

蛋白异常聚集是阿尔茨海默病(AD)和额颞叶痴呆(FTD)等许多神经退行性疾病的病理细胞标志,其中 tau 蛋白正在聚集,形成神经纤维缠结(NFT),并在神经元之间传播。这些过程与疾病进展和认知功能下降有关。各种治疗方法都旨在预防或减少神经元中的tau聚集。人类诱导多能干细胞(hiPSCs)是神经科学发现中非常有价值的工具,因为它们为体外研究提供了可能无限量的受疾病影响的细胞类型,包括皮质神经元。我们利用 hiPSC 衍生的神经元,经过慢病毒转导后表达易发生聚集的荧光标记版人类 tau 蛋白,生成了 tau 聚集的体外模型。在加入重组声化成对螺旋丝(sPHFs)形式的 tau 种子后,神经元显示出强大的、类似疾病的 tau 蛋白聚集。该模型被开发为一种基于平板的高含量筛选测定法,并与图像分析算法相结合,以评估小分子或基因扰动对 tau 的影响。我们的研究表明,该试验可用于评估小分子或筛选靶向化合物库。通过使用基于 siRNA 的基因敲除,可以评估感兴趣的基因,我们还可以通过在该测定中筛选近 100 种去泛素化酶 (DUB),证明可以筛选靶向基因库。该测定使用基于成像的读数,时间相对较短,可量化 tau 的聚集程度,还能评估细胞活力。此外,它还能很容易地适用于不同的 hiPSC 株系或神经元亚型。总之,这种复杂而高度相关的方法可以每周在多个项目的筛选漏斗中常规应用,产生数据的周转时间约为五周。
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引用次数: 0
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SLAS Discovery
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