Network Proximity-based computational pipeline identifies drug candidates for different pathological stages of Alzheimer's disease.
Network Proximity-based computational pipeline identifies drug candidates for different pathological stages of Alzheimer's disease.
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DOI：
10.1016/j.csbj.2023.02.041
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发表时间：
2023
影响因子：
6
通讯作者：
Fang, Jiansong
中科院分区：
文献类型：
--
作者：
Wu, Qihui;Su, Shijie;Cai, Chuipu;Xu, Lina;Fan, Xiude;Ke, Hanzhong;Dai, Zhao;Fang, Shuhuan;Zhuo, Yue;Wang, Qi;Pan, Huafeng;Gu, Yong;Fang, Jiansong
尽管对阿尔茨海默病 (AD) 进行了大量投资，但仍然没有针对 AD 的疾病缓解疗法 (DMT)。一个主要原因是临床“一刀切”方法的局限性，仅基于临床诊断的相同AD治疗方法不太可能取得良好的临床疗效。近年来，基于多组学数据的计算方法为药物发现提供了前所未有的机会，因为它们可以大大降低成本并提高效率。在这项研究中，我们打算通过计算重新利用美国食品和药物管理局 (FDA) 批准的药物来确定 AD 不同病理阶段的潜在候选药物。首先，我们收集了三个不同 AD 病理阶段的基因表达数据，包括轻度认知障碍 (MCI) 和 AD 早期和晚期阶段 (EAD、LAD)。接下来，我们利用网络邻近度方法量化了药物靶标网络和 AD 模块之间的网络距离，并确定了 193 个与 AD 具有显着关联的候选药物。检索以往的文献证据后，193种预测药物中有63种（32.6%）被证明对AD有治疗作用。我们根据 AD 患者单细胞转录组数据确定了这些候选药物可能发挥作用的特定脑细胞，进一步探索了这些候选药物的新作用机制 (MOA)。此外，我们选择了几种有希望的候选化合物，它们可以穿过血脑屏障并具有已证实的神经保护作用，并随后确定了这些化合物的抗氧化活性。实验结果表明，硫唑嘌呤降低了APP-SH-SY5Y细胞中活性氧（ROS）和丙二醛（MDA）水平，并提高了超氧化物歧化酶（SOD）活性。最后，我们通过网络分析破译了硫唑嘌呤对抗 AD 的潜在 MOA，并通过蛋白质印迹验证了几种凋亡相关蛋白（Caspase 3、Cleaved Caspase 3、Bax、Bcl2）。总之，本研究提出了一种利用组学数据进行 AD 药物再利用的有效计算策略，为药物发现和开发提供了新的视角。
Despite the massive investment in Alzheimer’s disease (AD), there are still no disease-modifying treatments (DMTs) for AD. One major reason is attributed to the limitation of clinical "one‐size‐fits‐all” approach, since the same AD treatment solely based on clinical diagnosis was unlikely to achieve good clinical efficacy. In recent years, computational approaches based on multiomics data have provided an unprecedented opportunity for drug discovery since they can substantially lower the costs and boost the efficiency. In this study, we intended to identify potential drug candidates for different pathological stages of AD by computationally repurposing Food and Drug Administration (FDA) approved drugs. First, we assembled gene expression data from three different AD pathological stages, which include mild cognitive impairment (MCI) and early and late stages of AD (EAD, LAD). We next quantified the network distances between drug target networks and AD modules by utilizing a network proximity approach, and identified 193 candidates that possessed significant associations with AD. After searching for previous literature evidence, 63 out of 193 (32.6%) predicted drugs were demonstrated to exert therapeutic effects on AD. We further explored the novel mechanism of action (MOA) for these drug candidates by determining the specific brain cells they might function on based on AD patient single cell transcriptomic data. Additionally, we selected several promising candidates that could cross the blood brain barrier together with confirmed neuroprotective effects, and subsequently determined the antioxidative activity of these compounds. Experimental results showed that azathioprine decreased the reactive oxygen species (ROS) and malondialdehyde (MDA) levels and improved the superoxide dismutase (SOD) activity in APP-SH-SY5Y cells. Finally, we deciphered the potential MOA of azathioprine against AD via network analysis and validated several apoptosis-related proteins (Caspase 3, Cleaved Caspase 3, Bax, Bcl2) through western blotting. In summary, this study presented an effective computational strategy utilizing omics data for AD drug repurposing, which provides a new perspective for drug discovery and development.
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影响因子：
4
作者：
Hanyu, Haruo;Hirao, Kentaro;Iwamoto, Toshihiko
通讯作者：
Iwamoto, Toshihiko
DOI：
10.1111/cts.12491
发表时间：
2018-03
期刊：
Clinical and translational science
影响因子：
--
作者：
Cummings J
通讯作者：
Cummings J
影响因子：
25
作者：
Grubman, Alexandra;Chew, Gabriel;Polo, Jose M.
通讯作者：
Polo, Jose M.
影响因子：
6.7
作者：
Fang J;Cai C;Chai Y;Zhou J;Huang Y;Gao L;Wang Q;Cheng F
通讯作者：
Cheng F
影响因子：
3.6
作者：
Jin, Da-Qing;Sung, Jin-Young;Han, Jung-Soo
通讯作者：
Han, Jung-Soo