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摘要:Inhibiting host-cell protein functions using established drug compounds with excellent safety profiles produces promising antiviral effects with greater flexibility for candidate targets, decreased incidence of resistant variants and favorable balance of costs and risks. Recent genomic methods generated a large number of robust host dependency factors, providing numerous candidates for discovery of novel drug targets and antivirals. However, there is a lack of a global view of the landscape of different viruses and their potential host factors targeted by known drugs. Development of repositioned antivirals is currently limited to discrete study of single virus. Here, we integrated comprehensive published data among viruses, host factors and known drugs and presented a large-scale drugvirus network(DVN) to predict novel antiviral therapeutics on the basis of matching host factors for viral infections and drug targets. We grouped viral infections from a new perspective based on virus targeted host proteins(VTHPs) according to their enriched signaling pathways. Elucidating superiority of nonessential membrane and hub proteins as potential targets of repositioned drugs, we proposed 543 druggable candidate VTHPs. We then predicted new antiviral indications and therapeutic potentials for 703 FDA-approved small-molecule drugs, exploring their potential as broad-spectrum antivirals. The in vitro and in vivo tests confirmed the repositioned indications for bosutinib, maraviroc and dextromethorphan against herpes simplex virus-1(HSV-1), hepatitis B virus(HBV) and influenza A virus(IAV), respectively for their potency in non-toxic concentrations. In addition, efficacy of their combinations with antivirals already in clinical use have been investigated and confirmed. Dextromethorphan in low doses turned out to be superior to high doses in both single and combined treatments. This study offers a systematic and efficient bioinformatics way to discover novel host targets with higher potential and new antiviral indications for established drugs, which may facilitate their translation into clinical therapies for combating viral infections.
会议名称:

第九届亚洲毒理学大会暨中国毒理学会第八次中青年科技论坛

会议时间:

2021-10-20

会议地点:

中国浙江杭州

  • 专辑:

    医药卫生科技

  • 专题:

    药学

  • DOI:

    10.26914/c.cnkihy.2021.052611

  • 分类号:

    R965

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