基于表达谱印记关联网络的宿主靶向抗病毒药物重定位

Despite notable success of existing viral-inhibitor drugs for the treatment of some viral infections, they suffer from widespread drug-resistance problem due to the high mutation rates of virus. In addition, the narrow spectrum of action forms another difficulty for virus-directed strategy. An alternative promising antiviral approach is by using host-directed strategies. A large number of proven, druggable targets in host cells offer great flexibility for host-directed antiviral drug discovery. And most importantly, the host-directed antiviral drugs may provide a higher barrier to the development of resistance since the target proteins would not normally mutate in response to therapies. Another particularly great advantage for host-directed strategy is that there are wealth of approved and experimental drugs used for non-infectious diseases treatment can be exploited to find effective antiviral agent at relatively little cost and on a short timescale. The de novo drug development is a time-consuming, costly and risky procedure. Drug repurposing, which aim at identifying new uses for existing drugs, offers one of the best risk-versus-reward trade-off of the available drug development strategies. Driven by pharmaceutical companies, there has been a surge of interest in systematically elucidating new areas of application for known drugs. In addition to the economic considerations, the repurposing strategies may be especially attractive for the antiviral therapeutics in the control of infectious disease outbreak or bioterrorism defense. Although drug repurposing represents an efficient approach to drug discovery, most of success stories in this field were actuarially accidental findings; a good deal of new indications of exiting drugs may still under exploitation.In this project, based on the connectivity map of gene expression of viral infection, drug action and gene silence, we aim to construct a pipeline to predict host targets and repurposing antiviral drugs. The results about Dengue and other two virus will be verified by in vitro and in vivo experiment.

以病毒蛋白为靶的抗病毒药物面临易产生耐药等诸多问题，宿主分子靶向已经.成目前抗病毒药物研究的重要策略，宿主靶标的辨识是宿主靶向药物设计的关键，采用已知药物重定位是宿主靶向抗病毒药物研发的快捷有效途径。近年来，病毒感染、基因沉默、药物作用机理等表达谱数据快速积累，为宿主靶向抗病毒药物靶标的计算辨识和药物重定位预测提供了很好的基础。本项目拟基于表达谱印记比较方法，建立一种在转录组水平辨识抗病毒宿主靶标和已知药物的计算方法，挖掘病毒感染、宿主基因沉默、药物作用之间的相关性，预测具有抗病毒活性的已知药物，并在登革和EV71病毒上进行实验验证。

病毒性疾病严重危害人类健康，历史上几次全球范围的病毒性疾病流行给人类带来了深重的灾难。近年来甲型H1N1 流感、高致病性禽流感、SARS 等病毒的肆虐造成了极大的社会恐慌和难以估算的经济损失。抗病毒药物在近20 年来有了很大发展，但是，这些药物通常以病毒本身的蛋白为靶标，病毒通过频繁的变异极易导致抗病毒药物失效。此外，由于不同种类的病毒分子结构差异较大，以病毒本身蛋白为靶的药物很难实现广谱。由于病毒是严格的细胞内寄生生物，可以通过抑制与病毒生存密切相关的宿主蛋白来达到抗病毒的目的，同时解决耐药问题。近年来，宿主靶向和宿主-病毒联合靶向策略成为抗病毒药物研究的重要发展方向。宿主靶向策略的一个重要优势是可以充分利用目前已知的各种非抗病毒药物，通过药物重定位（即发现药物的新适应症）筛选和模拟创新，用相对较小的代价发现新的抗病毒药物。表达谱印记是用一定数量显著差异表达基因的有序集合代替原始的基因表达谱，既完整地体现了细胞状态，又有效避免了基因表达涨落和芯片实验噪声的影响。通过细胞或组织在生理、病理、药物治疗等状态下基因表达谱印记的比对，可以建立起疾病-疾病、疾病-药物、药物和药物之间的联系，为药物靶标的发现和药物重定位提供重要线索。本课题通过开发基因表达谱印记比较方法，建立了在转录组水平辨识抗病毒宿主靶标和已知药物的计算方法，挖掘了病毒感染、宿主基因沉默、药物作用之间的相关性，预测了一些病毒感染依赖的关键宿主和具有抗病毒活性的已知药物，通过细胞学实验评价了针对HBV、HSV-1、IAV H1N1和IAV H3N2病毒的潜在抗病毒药物的活性，发现了一些具有细胞学活性的抗病毒已知药物，为进一步的药物重定位和模拟创新提供了重要的线索。