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基于表型的药物筛选：一种对调节斑马鱼M细胞再生的化合物进行分类和鉴定的策略。

Phenotype-based drug screening: An strategy to classify and identify the chemical compounds modulating zebrafish M-cell regeneration.

作者信息

Kumari Ankita, Zeng Xin-An, Rahaman Abdul, Farooq Muhammad Adil, Huang Yanyan, Alee Mahafooj, Yao Runyu, Ali Murtaza, Khalifa Ibrahim, Badr Omnia

机构信息

School of Food Science and Engineering, South China University of Technology, Guangzhou, China.

Guangdong Key Laboratory of Food Intelligent Manufacturing, Foshan University, Foshan, Guangdong, China.

出版信息

Front Mol Biosci. 2022 Oct 24;9:984461. doi: 10.3389/fmolb.2022.984461. eCollection 2022.

DOI:10.3389/fmolb.2022.984461
PMID:36353729
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9637979/
Abstract

Several disease-modulatory FDA-approved drugs are being used in patients with neurodegenerative diseases. However, information on their toxicity-related profiles is very limited. Therefore, measurement of drug toxicity is essential to increase the knowledge of their side effects. This study aimed to identify compounds that can modulate M-cell regeneration by causing neuro-protection and -toxicity. Here, we developed a simple and efficient assay using Tg (hsp: Gal4FF62A; UAS: nfsB-mCherry) transgenic zebrafish larvae. Interestingly, the phenotype-based drug screening approach, we rapidly investigated 1,260 compounds from the United States drug collection and validated these in large numbers, including 14 compounds, that were obstructing this regeneration process. Next, 4 FDA-approved drugs out of 14 compounds were selected as the lead hits for analysis to clarify their binding patterns with PTEN and SOCS3 signaling due to their significant potential in the inhibition of axon regeneration. Molecular docking studies indicated good binding affinity of all 4 drugs with the respective signaling molecules. This may point to PTEN and SOCS3 as the signaling molecules responsible for reducing axon regeneration. Moreover, the acute effect of compounds in reducing M-cell regeneration delineated their toxic effect. In conclusion, our along with screening strategy will promote the rapid translation of new therapeutics to improve knowledge of the toxicity profile of approved/non-approved drugs efficiently.

摘要

几种经美国食品药品监督管理局（FDA）批准的疾病调节药物正在用于神经退行性疾病患者。然而，关于它们毒性相关特征的信息非常有限。因此，测量药物毒性对于增加对其副作用的了解至关重要。本研究旨在鉴定能够通过引起神经保护和毒性来调节M细胞再生的化合物。在此，我们利用Tg（hsp:Gal4FF62A；UAS:nfsB-mCherry）转基因斑马鱼幼虫开发了一种简单有效的检测方法。有趣的是，基于表型的药物筛选方法，我们快速研究了来自美国药物库的1260种化合物，并对其中大量化合物进行了验证，包括14种阻碍这种再生过程的化合物。接下来，从这14种化合物中选择了4种经FDA批准的药物作为主要研究对象进行分析，以阐明它们与PTEN和SOCS3信号传导的结合模式，因为它们在抑制轴突再生方面具有显著潜力。分子对接研究表明，所有4种药物与各自的信号分子都具有良好的结合亲和力。这可能表明PTEN和SOCS3是负责减少轴突再生的信号分子。此外，化合物在减少M细胞再生方面的急性作用描绘了它们的毒性作用。总之，我们的筛选策略将促进新疗法的快速转化，以有效地提高对已批准/未批准药物毒性特征的了解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/569c300d3b01/fmolb-09-984461-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/0984a75a07e4/fmolb-09-984461-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/e96080722c2e/fmolb-09-984461-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/95489ce0749a/fmolb-09-984461-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/9fac0c0a9896/fmolb-09-984461-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/147bd56c69cf/fmolb-09-984461-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/b7a95be17f23/fmolb-09-984461-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/aa0943e2babc/fmolb-09-984461-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/82e927904e94/fmolb-09-984461-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/569c300d3b01/fmolb-09-984461-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/0984a75a07e4/fmolb-09-984461-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/e96080722c2e/fmolb-09-984461-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/95489ce0749a/fmolb-09-984461-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/9fac0c0a9896/fmolb-09-984461-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/147bd56c69cf/fmolb-09-984461-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/b7a95be17f23/fmolb-09-984461-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/aa0943e2babc/fmolb-09-984461-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/82e927904e94/fmolb-09-984461-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d267/9637979/569c300d3b01/fmolb-09-984461-g009.jpg

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