基于关联网络的宿主靶向抗病毒药物重定位研究

发布时间：2018-06-15 20:44

本文选题：宿主靶向抗病毒 + 药物重定位　；参考：《中国人民解放军军事医学科学院》2015年博士论文

【摘要】：时至今日,病毒感染引发的疾病仍是人类健康和公共卫生的一大威胁,全球每年死于病毒感染性疾病的人数以百万计。面对慢性病毒感染性疾病的流行、急性新出现病毒疫情的爆发、一度消失或已被控制病毒的“死灰复燃”以及生化武器可能被恐怖袭击利用这些威胁,迫切需要提出安全快捷有效的抗病毒策略。传统的病毒靶向策略存在诸多问题,主要包括靶标选择空间有限、病毒易产生耐药性、以病毒为靶标药物的抗病毒谱较窄等。针对这些弊端提出的宿主靶向抗病毒策略,不仅具有靶标选择空间大、不易产生耐药性、有望实现广谱抗病毒的优势,更为重要的是,为利用已知药物抗病毒打开了广阔的空间。由于宿主靶向抗病毒策略一个突出的优势就在于存在大量靶向宿主蛋白的已知药物,所以宿主靶向抗病毒药物重定位策略应运而生。利用药物重定位的方法可以充分利用已知药物,缩短周期、节约成本、降低风险,对于抗病毒药物研发来说,不仅能够满足反恐和突发疫情控制的需要,为病毒性传染病的防控提供应急药物解决方案,还能为通过模拟创新手段开发新药奠定基础。另外,除了为人熟知的人工合成药物,制药产业也将目光转向了天然药物。由于天然药物具有经济有效、安全性较高等优势,同时顺应多向药理学的思路,近年来制药产业对天然药物的研究蓬勃发展,天然药物在当前药物研发领域表现出巨大的潜力。天然药物对于新药研发具有很大的价值和指导意义,在已有抗病毒药物中来源于天然产物的化合物所占比例也很高,可见天然药物用于抗病毒治疗前景广阔。本文综合应用关联网络的方法,收集整合了病毒感染过程中的病毒靶标蛋白(Virus Targeting Proteins,VTPs)和关键宿主因子(Essential Host Factors,EHFs),结合药物-靶标关联数据、天然药物成分-靶标关联数据和蛋白质相互作用数据,以病毒、化合物共用靶标为基础关联已知药物化合物和病毒,评估已知化合物重定位于抗病毒应用的可能性,并进一步探索了它们用于广谱抗病毒的潜力。本文首先收集整合了来源于文献报道的病原体感染EHF,在此基础上建立了EHFPI数据库。其次将整合的病毒感染EHF数据集与来自Vir Host Net数据库的VTP数据集进行比较分析,阐述这两种病毒感染宿主因子的联系与区别。在此基础上基于病毒与Drug Bank数据库药物的共用靶标建立病毒-药物关联网络,系统分析已知药物对于病毒感染进行防治的可能性,并进一步探讨已知药物应用于广谱抗病毒的潜力。此后我们还收集整理了来自HIT数据库的天然药物及其靶标信息,与Drug Bank数据库靶标进行对比,计算分析天然药物靶标的富集情况,预测天然药物在治疗人类复杂疾病中的倾向与趋势。最后以相同的思路基于共用靶标探讨了天然药物重定位于抗病毒及广谱抗病毒的可能性。基于系统生物学和分子网络,以计算的方法理性预测已知药物及天然药物成分重定位于抗病毒的潜力,大规模系统地评估宿主靶向抗病毒已知化合物重定位的可能性可以为药物的发现与设计提供新的方法和策略。本文第一章综述了目前抗病毒药物研究的背景、方法与现状,提出了宿主靶向策略和药物重定位运用于抗病毒药物研发的若干关键问题,阐述了论文的主要研究内容、组织形式结构和技术路线。高通量筛选与计算技术的飞速发展极大地促进了微生物学发展水平,使微生物学家可以更为全面地解读病原体-宿主相互作用关系。通过基因组规模的RNA干扰(RNA interference,RNAi)筛选实验,可以得到病原体感染的EHF,敲除它们会严重影响病原体在宿主体内的生存和复制。论文第二章展示了我们手动收集整合的病原体感染宿主的EHF及其相关信息,在此基础上我们建立了EHFPI生物信息学数据库及相关分析资源。EHFPI数据库包含了25种临床上重要的病原体种类的4634个EHF基因及其对应的蛋白质,展示了相关论文、筛选实验、病原体和表型注释等信息。另外,EHFPI数据库还提供了6种有效的数据整合分析工具,以此促进我们对EHF基因及其对应产物生物学意义的理解,同时从多个角度阐释蛋白质相互作用网络、药物靶标与疾病之间的关系。我们还进一步选取了通过基因组规模RNAi筛选实验得到的病毒感染宿主的EHF。除此之外,还有一类重要的宿主因子即VTP,它们与病毒直接相互作用以保障病毒在细胞内的生存。然而,这两种宿主因子之间的联系却很少被研究。论文第三章以人类免疫缺陷病毒1型(Human Immunodeficiency Virus-1,HIV-1)和流行性感冒A型病毒(influenza A virus,IAV)这两种病毒的感染为模型,对其EHF和VTP集合进行比对分析,发现两种病毒EHF与VTP的重合程度非常小,二者都具有明显的差异基因表达,调控方向一致。EHF与VTP都倾向于占据人类蛋白质相互作用网络上具有拓扑重要性的位置,两者之间倾向于直接相互作用。我们还针对这两种病毒识别出一些连接度比较大的EHF和VTP。进一步研究发现,对于EHF与VTP共通路的情形,多数EHF倾向于位于VTP上游起调节作用,以此强调了EHF在调节过程中的重要意义。由于当前主流的病毒靶向策略存在一些困难,抗病毒药物研发仍然充满挑战。宿主靶向抗病毒策略具有靶标选择空间大、不易产生耐药性、容易实现广谱抗病毒等优势,同时,有大量现成的药物可以使用,避免了全新药物开发周期漫长、耗资巨大、风险较高等弊端。因此,宿主靶向抗病毒药物重定位策略已经成为抗病毒药物研发领域一个重要的方向。论文第四章基于对已有药物-靶标互联关系和病毒-宿主相互作用关系知识的整合,力图揭示哪些已经验证的病毒生存依赖的宿主蛋白可能被现有药物干扰,进而通过整合病毒-宿主蛋白相互作用网络和药物-靶标关系网络构建了药物-病毒关系网络,系统梳理了可直接或间接作用于病毒依赖的宿主蛋白的已知药物,给出了对现有药物宿主靶向抗病毒潜力的系统评估,并进一步讨论了通过已知药物进行广谱抗病毒的可能性。除了为人熟知的化学合成药物,天然药物或来源于天然产物的化合物在研究领域和制药产业中也具有特别重要的意义。天然药物已被人类使用了很长时间,由于其经济有效、安全性高、符合现代多向药理学的理念,因而对现代药物开发也具有重要的价值,并且在现代药物治疗中取得了突出的成绩。论文第五章主要以探索天然药物在复杂疾病治疗中的潜在应用为目的,应用大规模靶标分析的方法,从靶标蛋白相关通路和疾病分类的角度将HIT数据库提供的天然药物靶标与Drug Bank数据库提供的合成药物靶标进行对比,建立了天然药物成分-直接靶标关系二分网络。我们从当前药物研发趋势的视角讨论了该网络的关键特性和天然药物及其靶标之间的关联,发现天然药物可能成为潜在的抗癌药物。鉴于天然药物具有许多独特的优势,又契合现代药物研发领域多向药理学的思路,探索天然药物在宿主靶向抗病毒药物重定位中的应用可能带来新的发现。论文第六章回顾整合了关于病毒、已知天然药物成分及其靶标蛋白的数据信息,基于共用靶标探讨天然药物成分与病毒之间的二分关系进而建立了天然药物成分-病毒关系网络。在此基础上讨论了天然药物成分重定位于宿主靶向抗病毒的可能性,评估了它们用于广谱抗病毒的潜力。大规模网络分析表明,尽管总体上看,天然药物成分重定位于广谱抗病毒空间有限,但靶向被多种病毒共用靶标蛋白的药物成分更有可能成为潜在的广谱抗病毒药物。论文最后对全文所述工作进行了简要总结,并对下一步的工作计划进行了展望。
[Abstract]:Today, the disease caused by virus infection is still a major threat to human health and public health. Millions of people die of virus infection in the world every year. In the face of the epidemic of chronic viral infection, the outbreak of acute new virus epidemic, once disappeared or has been controlled by the "resurgence" and biochemical weapons. It is possible to use these threats by terrorist attacks, and it is urgent to propose a safe, efficient and effective antiviral strategy. There are many problems in the traditional virus targeting strategy, including the limited space of target selection, the susceptibility of the virus to drug resistance, the narrower antiviral spectrum of the virus as the target drug, and the host targeting against these disadvantages. Virus strategy not only has large target selection space, not easy to produce drug resistance, it is expected to realize the advantages of broad-spectrum antivirus. More importantly, it opens wide space for the use of known antiviral drugs. Because a prominent advantage of host targeting antiviral strategy lies in the existence of a large number of known drugs targeting the host protein, so the host has a large number of known drugs. The repositioning strategy of the main target to antiviral drugs came into being. The method of drug repositioning can make full use of the known drugs, shorten the cycle, save the cost and reduce the risk. For the research of antiviral drugs, it can not only meet the needs of anti-terrorism and outbreak control, but also provide an emergency drug solution for the prevention and control of viral infectious diseases. In addition, in addition to the known synthetic drugs, the pharmaceutical industry will also turn to natural drugs. The pharmaceutical industry has studied natural drugs in recent years because of its economic efficiency, high safety and multi direction pharmacology. Natural drugs have great potential in the field of drug research and development. Natural drugs have great value and guiding significance for the research and development of new drugs. The proportion of compounds derived from natural products in the existing antiviral drugs is also very high. It is obvious that natural drugs are widely used in antiviral treatment. This article is a comprehensive application. The combined network method collects and integrates virus target protein (Virus Targeting Proteins, VTPs) and key host factors (Essential Host Factors, EHFs) in the process of virus infection, combined with drug target related data, natural drug components - target related data and protein interaction data, based on virus and compound target as the basis. Associated with known drug compounds and viruses, the potential of known compounds relocated to antiviral applications was evaluated, and their potential for broad-spectrum antiviral treatment was further explored. First, a EHFPI database was established on the basis of an integrated pathogen infection EHF from the literature. Secondly, the integrated virus infection EHF was established. The data set and the VTP data set from the Vir Host Net database are compared and analyzed to explain the relationship and difference between the two virus infected host factors. Based on this, the virus drug association network is set up based on the common target of the virus and Drug Bank database drugs, and the possibility of prevention and control of the virus infection by known drugs is systematically analyzed. The potential of known drugs used in broad-spectrum antivirus was further explored. After that, we collected and collated the information of natural drugs and targets from the HIT database, compared with the target of Drug Bank database, calculated and analyzed the enrichment of natural drug targets, and predicted the tendency and trend of natural drugs in the treatment of human complex diseases. Finally, the possibility of relocating natural drugs to antiviral and broad-spectrum antiviral agents is discussed based on common targets. Based on systematic biology and molecular networks, the potential of the known drugs and natural drug components relocated to the antiviral potential is rationally predicted and a large systematic assessment of the known host targeted antiviral activity is made in a large scale. The possibility of relocation of compounds can provide new methods and strategies for the discovery and design of drugs. In the first chapter, the background, methods and status of the research on antiviral drugs are reviewed. The key problems of host targeting strategy and drug relocation in the research and development of antiviral drugs are put forward, and the main research in this paper is expounded. The development of high throughput screening and computing technology has greatly promoted the level of Microbiology, enabling microbiologist to interpret the relationship between pathogen and host more comprehensively. The RNA interference (RNA interference, RNAi) screening experiments on the scale of the genome can obtain the sense of pathogen. The second chapter of the paper shows that we manually collect the EHF and related information of the infected host by manually collecting the integrated pathogens, and on this basis we have established the EHFPI bioinformatics database and the related analysis resource.EHFPI database containing 25 kinds of clinical weights. The 4634 EHF genes and their corresponding proteins of the pathogen species show relevant papers, screening experiments, pathogens and phenotypic annotations. In addition, the EHFPI database also provides 6 effective data integration tools to promote our understanding of the biological significance of the EHF gene and its products and from multiple angles. To explain the relationship between protein interaction network, drug target and disease, we have further selected the EHF. of the host virus infected by the genome scale RNAi screening experiment. In addition, there is a class of important host factors, VTP, which interact directly with the virus in order to ensure the survival of the virus in the cell. The relationship between the two host factors is rarely studied. The third chapter of the paper is the model of the two viruses, the Human Immunodeficiency Virus-1 (HIV-1) and the influenza A virus (influenza A virus, IAV), and the comparison and analysis of its EHF and VTP collection, and the discovery of the two virus EHF and the weight of the virus. The degree of coincidence is very small, and all of the two have distinct differentially expressed genes. The regulation direction.EHF and VTP tend to occupy the position of topological importance on the human protein interaction network, and they tend to interact directly with each other. We also identify some of the two kinds of viruses with larger EHF and VTP.. The step study shows that most EHF tends to adjust to the upstream of VTP in the case of EHF and VTP common path, which emphasizes the importance of EHF in the process of regulation. It is not easy to produce drug resistance and easy to achieve broad-spectrum antiviral and other advantages. At the same time, there are a large number of available drugs that can be used to avoid the long development cycle of new drugs, huge cost and high risk. Therefore, the repositioning strategy of host targeting antiviral drugs has become an important direction in the field of antiviral drugs research and development. The fourth chapter, based on the integration of the existing drug target interconnections and the knowledge of virus host interaction, tries to reveal which host proteins that have been verified to be dependent on the survival of the virus may be interfered by the existing drugs, and then construct a drug disease by integrating the virus host protein interaction network and the drug target relationship network. The drug relationship network, which systematically combs known drugs that can directly or indirectly acts on virus dependent host proteins, gives a systematic assessment of the potential of the current drug host targeting antiviral potential, and further discusses the possibility of broad-spectrum antiviral use of known drugs. Compounds derived from natural products are also of particular importance in the field of research and the pharmaceutical industry. Natural drugs have been used for a long time by human beings. Because of their economic efficiency, high safety, and modern multidirectional pharmacology, it is also of great value to modern drug development and is taken in modern drug treatment. The fifth chapter of the paper aims at exploring the potential application of natural drugs in the treatment of complex diseases. By using the method of large-scale target analysis, the synthetic drug targets provided by the natural drug target of the HIT database and the Drug Bank database provided by the target protein related pathway and the disease classification are carried out. In contrast, a natural drug component direct target relationship is established in the two sub network. From the perspective of current drug development trends, we discuss the key characteristics of the network and the association between natural drugs and their targets, and find that natural drugs may become potential anticancer drugs. The application of natural drugs in the relocation of host targets to antiviral drugs may bring new discoveries. The sixth chapter of the paper reviewed and integrated the data information about the virus, the known components of natural drugs and their target proteins, and explored the relationship between the natural drug components and the virus based on the common target. The two sub relationship then established the natural drug component virus relationship network. On this basis, the possibility of relocating the natural drug components at the host target was discussed, and the potential of their application to the broad-spectrum antivirus was evaluated. Large-scale network analysis showed that, in general, the drug components were relocated in the broad-spectrum antiviral space. It is limited, but the drug components that target the target protein of various viruses are more likely to be potential broad-spectrum antiviral drugs. Finally, the paper briefly summarizes the work described in the full text, and looks forward to the next work plan.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R978.7

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