Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs.
Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs.
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DOI：
10.1177/20402066211036822
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发表时间：
2021-01
影响因子：
--
通讯作者：
Nimgaonkar VL
中科院分区：
文献类型：
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作者：
Zheng W;D'Aiuto L;Demers MJ;Muralidaran V;Wood JA;Wesesky M;Chattopadhyay A;Nimgaonkar VL
药物再利用是识别具有新作用的药物的一种经济有效的策略。我们寻找对单纯疱疹病毒1型(HSV-1)具有抑制活性的药物。我们的策略利用了HSV-1感染细胞培养产生的基因表达数据，这些数据与药物对基因表达的影响相匹配。用BaseSpace关联引擎(Illumina®)分析HSV-1感染和未感染神经元的基因表达数据。基于一般信号反转原理(SRP)，我们假设候选抗病毒药物对基因表达的影响与HSV-1感染诱导的作用完全相反(负相关)。我们最初确定了能够诱导基因表达变化的化合物，这些化合物与HSV-1感染所导致的变化相反。在非洲绿猴肾上皮细胞(Vero细胞)中，最有希望的负相关药物(丙戊酸、Vorinostat)对HSV-1感染的进一步抑制作用不明显。接下来，我们测试了萝卜硫素和甲奈酮，它们显示出与病毒感染相似的效果(正相关)。有趣的是，萝卜硫素对Vero细胞中的单纯疱疹病毒1型感染有适度但显著的抑制作用(IC50 = 180.4 µM，p = 0.008)，但在进一步研究从诱导多能干细胞衍生的人神经前体细胞(NPC)中显示出毒性。这些结果揭示了常用的SRP策略在应用于新型抗病毒药物鉴定时的局限性，并突显了改进SRP策略以提高其实用性的必要性。
Drug repurposing is a cost-effective strategy to identify drugs with novel effects. We searched for drugs exhibiting inhibitory activity to Herpes Simplex virus 1 (HSV-1). Our strategy utilized gene expression data generated from HSV-1-infected cell cultures which was paired with drug effects on gene expression. Gene expression data from HSV-1 infected and uninfected neurons were analyzed using BaseSpace Correlation Engine (Illumina®). Based on the general Signature Reversing Principle (SRP), we hypothesized that the effects of candidate antiviral drugs on gene expression would be diametrically opposite (negatively correlated) to those effects induced by HSV-1 infection. We initially identified compounds capable of inducing changes in gene expression opposite to those which were consequent to HSV-1 infection. The most promising negatively correlated drugs (Valproic acid, Vorinostat) did not significantly inhibit HSV-1 infection further in African green monkey kidney epithelial cells (Vero cells). Next, we tested Sulforaphane and Menadione which showed effects similar to those caused by viral infections (positively correlated). Intriguingly, Sulforaphane caused a modest but significant inhibition of HSV-1 infection in Vero cells (IC50 = 180.4 µM, p = 0.008), but exhibited toxicity when further explored in human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells. These results reveal the limits of the commonly used SRP strategy when applied to the identification of novel antiviral drugs and highlight the necessity to refine the SRP strategy to increase its utility.