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通过真实世界双边RNA测序数据构建遗传和表观遗传宿主-病毒网络以研究人类呼吸道合胞病毒发病机制并鉴定药物再利用生物标志物:系统生物学和深度学习方法

Genetic and Epigenetic Host-Virus Network to Investigate Pathogenesis and Identify Biomarkers for Drug Repurposing of Human Respiratory Syncytial Virus via Real-World Two-Side RNA-Seq Data: Systems Biology and Deep-Learning Approach.

作者信息

Hsu Bo-Wei, Chen Bor-Sen

机构信息

Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.

出版信息

Biomedicines. 2023 May 25;11(6):1531. doi: 10.3390/biomedicines11061531.

Abstract

Human respiratory syncytial virus (hRSV) affects more than 33 million people each year, but there are currently no effective drugs or vaccines approved. In this study, we first constructed a candidate host-pathogen interspecies genome-wide genetic and epigenetic network (HPI-GWGEN) via big-data mining. Then, we employed reversed dynamic methods via two-side host-pathogen RNA-seq time-profile data to prune false positives in candidate HPI-GWGEN to obtain the real HPI-GWGEN. With the aid of principal-network projection and the annotation of KEGG pathways, we can extract core signaling pathways during hRSV infection to investigate the pathogenic mechanism of hRSV infection and select the corresponding significant biomarkers as drug targets, i.e., TRAF6, STAT3, IRF3, TYK2, and MAVS. Finally, in order to discover potential molecular drugs, we trained a DNN-based DTI model by drug-target interaction databases to predict candidate molecular drugs for these drug targets. After screening these candidate molecular drugs by three drug design specifications simultaneously, i.e., regulation ability, sensitivity, and toxicity. We finally selected acitretin, RS-67333, and phenformin to combine as a potential multimolecule drug for the therapeutic treatment of hRSV infection.

摘要

人呼吸道合胞病毒(hRSV)每年感染超过3300万人,但目前尚无获批的有效药物或疫苗。在本研究中,我们首先通过大数据挖掘构建了一个候选宿主-病原体种间全基因组遗传和表观遗传网络(HPI-GWGEN)。然后,我们通过双边宿主-病原体RNA-seq时间序列数据采用反向动态方法来去除候选HPI-GWGEN中的假阳性,以获得真实的HPI-GWGEN。借助主网络投影和KEGG通路注释,我们可以提取hRSV感染期间的核心信号通路,以研究hRSV感染的致病机制,并选择相应的重要生物标志物作为药物靶点,即TRAF6、STAT3、IRF3、TYK2和MAVS。最后,为了发现潜在的分子药物,我们通过药物-靶点相互作用数据库训练了一个基于深度神经网络的DTI模型,以预测这些药物靶点的候选分子药物。通过同时依据调节能力、敏感性和毒性这三个药物设计规范对这些候选分子药物进行筛选后,我们最终选择阿维A、RS-67333和苯乙双胍联合作为治疗hRSV感染的潜在多分子药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e14/10295364/e342bfe4bd22/biomedicines-11-01531-g001.jpg

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