Hernández Thaís Del Rosario, Gore Sayali V, Kreiling Jill A, Creton Robbert
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
bioRxiv. 2023 Sep 14:2023.09.12.557235. doi: 10.1101/2023.09.12.557235.
Drug repurposing can accelerate drug development while reducing the cost and risk of toxicity typically associated with de novo drug design. Several disorders lacking pharmacological solutions and exhibiting poor results in clinical trials - such as Alzheimer's disease (AD) - could benefit from a cost-effective approach to finding new therapeutics. We previously developed a neural network model, Z-LaP Tracker, capable of quantifying behaviors in zebrafish larvae relevant to cognitive function, including activity, reactivity, swimming patterns, and optomotor response in the presence of visual and acoustic stimuli. Using this model, we performed a high-throughput screening of FDA-approved drugs to identify compounds that affect zebrafish larval behavior in a manner consistent with the distinct behavior induced by calcineurin inhibitors. Cyclosporine (CsA) and other calcineurin inhibitors have garnered interest for their potential role in the prevention of AD. We generated behavioral profiles suitable for cluster analysis, through which we identified 64 candidate therapeutics for neurodegenerative disorders.
药物重新利用可以加速药物开发，同时降低通常与从头设计药物相关的毒性成本和风险。一些缺乏药理学解决方案且在临床试验中效果不佳的疾病——如阿尔茨海默病（AD）——可能会受益于一种经济高效的方法来寻找新的治疗方法。我们之前开发了一种神经网络模型，即Z-LaP Tracker，它能够量化斑马鱼幼体中与认知功能相关的行为，包括在视觉和听觉刺激下的活动、反应性、游泳模式和视动反应。利用这个模型，我们对美国食品药品监督管理局（FDA）批准的药物进行了高通量筛选，以确定那些以与钙调神经磷酸酶抑制剂诱导的独特行为一致的方式影响斑马鱼幼体行为的化合物。环孢素（CsA）和其他钙调神经磷酸酶抑制剂因其在预防AD中的潜在作用而受到关注。我们生成了适合聚类分析的行为概况，通过这些概况我们确定了64种神经退行性疾病的候选治疗药物。
