| Viral infections and their associated diseases remain one of the major threats for public health till now responsible for millions of deaths annually. Indeed effective antiviral strategies are imperative for many contributing factors including the everincreasing morbidity of chronic viral infections, unexpected outbreaks of acute viral infections such as severe acute respiratory syndrome(SARS) and avian influenza and the potential and actual threats of viruses being used as bioterrorist weapons. In addition, the rising number of multidrug-resistant viruses, the emergence of new viruses and the resurgence of viruses once eradicated such as variola virus have added to the demand for new antiviral strategies. Despite the enormous success of traditional virus-directed drug targeting strategy, it suffers from several serious shortcomings. For instance, available drug targets are severely limited due to the relatively small genomes of viruses usually encoding few proteins. The continuing emergence of drug-resistant variants related to the low-fidelity replication mode and high mutation rates of viruses, as well as the narrow spectrum of action of current virus-directed therapies have also emphasized the need for the development of more effective antiviral therapeutic strategy. A new promising antiviral drug discovery paradigm has therefore emerged targeting host proteins crucial for viruses but not host cells. The estimated 600-1,500 host genes provide a wealth of pharmacologically exploitable targets compared with viral inhibitors. Moreover, this alternative therapeutic strategy may lower the risk of emergence of drug resistance for host proteins would not normally mutate as viral proteins. The host-directed antiviral therapy might also enable the development of novel broad-spectrum antiviral drugs based on mechanisms and targets shared among a wide range of viruses. Most importantly, the vast majority of existing drugs used as antihypertensive, antineoplastic or anti-inflammatory agents are host-directed and represent a group of potential effective antiviral agents. Therefore, an alternativeattractive antiviral strategy is by exploring possible host-directed antiviral therapeutics based on drug repositioning(DR). Repositioning of FDA-approved drugs expedites the development of novel therapies and makes pharmaceutical research and development(R&D) less costly. It is a more systematic strategy with reduced risks based on known safety and bioavailability of these licensed drugs. Perhaps more importantly, this repositioning approach provides a number of antiviral candidates for potential biological threats including naturally outbreak of viral diseases and engineered agents of bioterrorism and bioweapons. Exploitation of potential novel indications for existing licensed drugs combined with possible broad-spectrum antivirals is one of the promising accessible means to address these challenges. In addition, drug repurposing offers a platform allowing new drug discovery based on mimics innovation. On the other hand, the pharmaceutical industry is focusing on natural products simultaneously. A considerable amount of hindsight and evidence suggest that natural medicines offer an economical and rational alternative to conventional medicines. Herbal medicines are also generally recognized as safe and tolerant based on sufficient scientific evidence and actual therapeutic use over the long term. Herbal extracts with pharmacological activity based on multisite mechanisms of action seem to precede single-site chemical agents for the latter ones often fail in the fight against complex diseases. In the recent past, natural medicines comprise a considerable proportion of pharma research and health care system. Natural product-derived drugs are gaining worldwide recognition as a basis for pharmaceutical research and the belief in their efficacy is growing. There is evidence to suggest that herbal medicines continue to hold great promise in today’s era of drug research and development process, as they remain the most important source of known antiviral drugs.In this thesis, we integrated accumulated knowledge on drug-target associations, herbal component-target associations and protein-pretein interactions based on association network with manually curated virus targeting proteins(VTPs) and essential host factors(EHFs). We then evaluated the possibility of repositioning of known compounds as antiviral agents and their potential as broad-spectrum antivirals based on shared targets of viruses and components. Firstly, we constructed bioinformatics database and analysis resource EHFPI(Essential Host Factors for Pathogenic Infection) based on the collection of EHFs in pathogenic infections from text mining. We especially analysed EHFs in viral infection and VTPs and revealed the functional associations and differences of the two host factor(HF) types for viral infection. We then constructed the drug-virus network based on the shared targets bewteen viruses and Drug Bank drugs. We explored the possibility of FDA-approved drugs as potential antiviral agents systematically and evaluated their broad-spectrum antiviral activity. Further more, we analysed the enrichment of herbal targets in comparison with Drug Bank ones based on information of natrural products and their corresponding targets from HIT database. We illustrated the trends of natrural products in treatment of complex diseases of human and predicted their possible application in DR toward antiviral uses.Large-scale systematical analyses and evaluation on antivral potential of known components based on association network provide a computational and rational approach for development of antiviral strategies.In the first chapter, we summarized the background of current situation and common methods of pharmaceutical industry, and posed several cirtical issues in host-directed antiviral strategy and DR. We then developed the main contents of our work, organization and the related technical route of this paper were also presented.With the rapid development of high-throughput screening and computational technology, pathogen–host interactions can be interpreted more comprehensively by microbiologists. EHFs for pathogenic infections obtained by genome-wide RNA interference(RNAi) screens are host proteins essential for attachment, entry, replication or assembly of pathogens but not crucial for cellular survival. In the second chapter, we constructed the manually-curated bioinformatics database and analysis resource EHFPI with information on 4634 EHFs for 25 clinically important species of pathogenic infection. EHFPI contains detailed information about articles, screens, pathogens and phenotype annotation for these EHFs as well as other six effective analysis tools for data integration. Our attempt to explore the protein-protein interaction network and associations between drug targets and diseases improves the understanding ofbiological significance of EHFs.Genome-wide RNAi screens have greatly facilitated identification of EHFs for viral infections. However, little has been done to link EHFs with another important HF type, i.e., VTPs that viruses directly interact with for intracellular survival, hampering an integrative understanding of virus-host interactions. In the third chapter, we collected EHFs and VTPs for human immunodeficiency virus type 1(HIV-1) and influenza A virus(IAV) infections. The results show in general that despite limited overlap, EHFs and VTPs are both among the most differentially dysregulated genes in host transcriptional response to HIV and IAV infection, and notably they show consistency in regulation orientation. In human protein-protein interaction network, EHFs and VTPs both hold topological important positions at the global center, and importantly their direct interactions are statistically significant. We also identified the most extensive VTP-interacting EHFs(or EHF-interacting VTPs) for HIV-1 and IAV, respectively. Further, most EHFs are the upstream regulator of VTPs when mapped in the same signaling pathways. Collectively, these results provide insights into functional associations of identified HFs for viral infections, and highlight the regulating significance of EHFs.Disadvantages of the current antiviral therapies necessitate the development of novel strategy for virus infection treatment. A new promising antiviral drug discovery paradigm has therefore emerged targeting host proteins crucial for viruses but not host cells. A large number of proven, druggable targets in host cells offer great flexibility for host-directed antiviral drug discovery compared with the viral inhibitor approach. And most importantly, the host-directed antiviral drugs may provide a higher barrier to the development of resistance since the host target proteins would not normally mutate in response to therapies. By targeting common host proteins that are required for different viruses, it is also possible to develop novel broad-spectrum antiviral drugs with high resistance barriers. In addition, wealth of approved and experimental drugs used for non-infectious diseases treatment can be exploited to find effective antiviral agents at relatively little cost and on a short timescale. In the fourth chapter, we integrated the current knowledge about VTPs revealed by virus-host interactomes, EHFs identifiedby gene silence and drug-target relations to present here how many and which VTPs or EHFs can be perturbed by existing drugs, and then constructed a drug-virus network based on virus-host network and drug-target network illustrating the systematic association between viruses and drugs to assess the potential of existing drugs as antiviral agentsNatural products and natural product-derived drugs have proven to be valuable resources for development of modern pharmaceuticals besides well-known chemically synthesized compounds. For many centuries natural compounds have been used to treat or alleviate human diseases. It is believed that natural medicines provide a costeffective and rational alternative to drug therapeutics as well as an efficient discovery engine to the pharmaceutical industry. Herbal medicines are generally recognized as safe and tolerant based on multisite mechanisms of action, which turn out to be a smart and attractive strategic option to facilitate drug discovery process and are gaining worldwide recognition. In the fifth chapter, we aim to explore the therapeutic potential of natural products in the treatment of complex diseases on large-scale by targets analysis in the view of their related pathways and disease categories compared with those of drugs from Drugbank database. We generated a bipartite graph composed of herbal components from HIT database and their targets linked by herbal componenttarget binary associations. Key properties of herbal component-target network, including analysis of herbal targets from the perspective of current trends in drug development are discussed in this article. As we demonstrate, herbal components tend to become promising agents with potential anticancer activities.As mentioned previously, infectious diseases remain an important global problem in public health. The potentiality of herbs repositioning for host-directed antiviral therapy may bring new insights on antiviral strategies for the extraordinary advantages of natural products. In the sixth chapter, we reviewed the accumulated knowledge on interactions among viruses, known herbal components and their related target proteins and built a bipartite graph of herbal component-virus network(HV network) linked by herbal component-virus binary associations based on shared targets between them. We explored possibilities of herbal components as host-directed antiviral agents andevaluated their potential broad-spectrum antiviral activities. Large-scale network analyses demonstrated that herbal compounds associated with proteins targeted by many viruses could become potential broad-spectrum antiviral agents in spite of the limitation of broad-spectrum antiviral space in view of the overall situation.In the final part, a brief summary on the work is presented, and further plan is prospected at last. |
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