抗HIV新靶标的生物信息学发掘和实验验证

There are some problems such as drug resistance, side effects and limited targets for the current anti-HIV drugs. So, targeting host proteins has become an important strategy of anti-HIV drug research. A key issue for the design of anti-HIV drugs targeting host is how to select the targets which can be targeted by small molecules and have low toxicity from a large number of host proteins. Our study aims to discover new anti-HIV targets by integrating a variety of high-throughput data using bioinformatics methods and validate the targets by experiments. First, we have developed a fast and accurate method, named HIV-CDRUG, to predict small molecules with anti-HIV activity. In our method, the area under the ROC curve (AUC) is up to 0.93. We use our method HIV-CDRUG to predict small molecules from CHEMBL database with anti-HIV activity. Then, the hypergeometric distribution test was used to identify the host target genes which have significant enrichment of anti-HIV compounds. By integrating expression and RNAi data, we further assess whether these targets have the potential to treat AIDS. Finally, we will validate the high-potential anti-HIV targets and compounds by experiments. The discovery and validation of these new targets provides important ideas and guidance for the host targeted anti-HIV drug development.

鉴于现有抗HIV药物存在耐药性、毒副作用以及靶标有限等诸多问题，宿主靶向已经成为抗HIV药物研究的重要策略。宿主靶向抗HIV药物设计要解决的一个关键问题是如何从众多的宿主蛋白中选择可以被小分子靶向且低毒的抗病毒靶标。本项目旨在利用生物信息学方法整合多种高通量数据来发掘新的抗HIV靶标并进行实验验证。首先，我们开发了一种可以准确预测小分子抗HIV活性的新颖方法HIV-CDRUG，ROC曲线下面积（AUC）高达0.93。利用HIV-CDRUG预测CHEMBL数据库中具有抗HIV活性的小分子。然后，利用超几何分布检验来识别出显著富集抗HIV活性化合物的宿主靶基因，并进一步通过整合表达数据和RNAi数据来评估这些靶蛋白是否具有治疗艾滋病的潜力。最后挑选高潜力的抗HIV靶标及化合物进行实验验证。这些新靶标的发掘和验证可以为宿主靶向的抗HIV药物研发提供重要思路和指导。

鉴于现有抗HIV药物存在耐药性、毒副作用以及靶标有限等诸多问题，宿主靶向已经成为抗HIV药物研究的重要策略。在本项目的支持下，我们开发出预测化合物是否具有抗HIV活性的方法Anti-HIV Predictor及其网页服务器（http://bsb.kiz.ac.cn:70/hivpre）供相关研究人员使用。该方法准确率大于93%，ROC曲线下面积（AUC）大于0.958。利用Anti-HIV Predictor进行药物重定位，经过实验验证，最终我们发现了7个新的潜在的抗HIV药物。这7个药物的治疗指数均大于10，EC50在0.003到1.788μM之间。利用抗HIV活性预测和富集，我们鉴别出13个具有高潜力的人类靶点可以作为新的抗HIV靶点，它们对应的抑制剂具有实验验证的抗HIV活性。值得一提的是蛋白REN和CALCA抑制剂的抗HIV活性强于CCR5的抑制剂。这些新化合物和新靶标的发掘和验证可以为宿主靶向的抗HIV药物研发提供重要思路和指导。