基于转录组特征基因反向匹配方法发现抗流感病毒化合物BIX02189  

Discovering BIX02189 as a novel anti-influenza virus compound using transcriptome signature reversion strategy

作　　者：吴悠 陈姝冰 唐克 郭颖 WU You;CHEN Shu-bing;TANG Ke;GUO Ying(Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,新药作用机制与药效评价北京市重点实验室,北京100050 [2]中国医学科学院、北京协和医学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050

出　　处：《药学学报》2022年第10期3002-3010,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82204472);中国医学科学院医学与健康科技创新工程(2022-I2M-2-002,2021-I2M-1-028);天然药物活性物质与功能国家重点实验室开放课题(GTZK202109);新药作用机制研究与药效评价北京市重点实验室(BZ0150);北京协和医学院学科建设项目(201920200802)。

摘　　要：流感病毒是RNA病毒,分甲、乙、丙、丁4型,其中甲型流感病毒和乙型流感病毒可引发人类急性呼吸道疾病,全球每年约30万患者死于流感感染。流感病毒的生命周期高度依赖宿主,靶向宿主因子已经成为抗病毒药物研究的重要策略。本研究通过转录组特征基因反向匹配(transcriptome signature reversion,TSR)方法,计算获得干预多宿主因子的抗流感病毒化合物列表,评价列表中化合物体外抗流感病毒活性,最终获得活性化合物BIX02189。结果显示,BIX02189具有广谱抗流感病毒活性,抗甲流病毒H1N1(A/Puerto Rico/8/1934)和乙流病毒(B/江西新建/BV/39/2008)的半数有效浓度(half maximal effective concentration,EC_(50))分别为17.1和9.4μmol·L^(-1),其中抗甲流活性优于利巴韦林(97.9μmol·L^(-1))。转录组间无监督学习相似性成簇分析显示,BIX02189的抗流感病毒主要机制可能通过干预Raf/MEK/ERK通路,实现对流感病毒颗粒的生成和释放的阻断。Influenza virus is an RNA virus that classified into 4 types,A,B,C,and D,where influenza A and B virus infection may cause human acute respiratory tract infection and nearly 0.3 million deaths annually.The life cycle of influenza virus infection is highly dependent on the host response,demonstrating an important strategy of developing anti-influenza agents that target the host factors.This research utilized a transcriptome signature reversion(TSR)strategy to discover a list of multi-host-factor-target anti-influenza agents and determined their antiinfluenza activities in vitro.BIX02189 was discovered and exhibited broad spectrum anti-influenza activity,with half maximal effective concentration(EC_(50))of 17.1μmol·L^(-1)-1against influenza A virus H1N1(A/Puerto Rico/8/1934)and 9.4μmol·L^(-1)for influenza B virus(B/Jiangxi Xinjian/BV/39/2008).The anti-influenza A virus activity of BIX01289 is stronger than the positive control ribavirin with EC_(50)of 97.9μmol·L^(-1)for influenza A virus H1N1(A/Puerto Rico/8/1934).According to the unsupervised transcriptomic profile similarity clustering analysis,BIX02189 was considered to inhibit viral protein synthesis and release of influenza virus mainly through inhibiting the Raf/MEK/ERK cascade,revealing its potential mechanism of inhibiting influenza virus infection.

关 键 词：流感病毒 宿主因子 化合物扰动细胞转录特征基因 转录组特征基因反向匹配 BIX02189 

分 类 号：R965.1[医药卫生—药理学]