HIV-1整合酶（IN）和逆转录酶（RT），是HIV生命复制周期中的必需关键酶，成为设计抗HIV药物的重要靶点。本项目基于Morphy“一药多靶点”设计新策略，拟将前期研究获得的QCA类IN抑制剂和DAPY类RT抑制剂进行重叠整合，获得系列QCA-DAPYs杂合物。并将这些杂合物分别与IN、RT进行对接研究，筛选能够同时在两种靶酶结合口袋均可形成正确空间取向的化合物，以此设计HIV-1双靶点抑制剂QCA-DAPYs杂合物。通过化学手段合成目标物，并对目标物进行IN、RT酶水平及细胞水平的抗HIV活性筛选，建立3D-QSAR模型，筛选1-3个高活性强抗耐药性化合物进行离体生物代谢稳定性研究。本项目力争从中发现1-2个高活性、强抗耐药性、且代谢稳定的抗HIV新药候选物，为研发具有我国自主知识产权的抗HIV药物提供理论基础和技术支持。

Human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) and integrase (IN) are ones of the virally encoded enzymes required for replication and therefore represent rational targets for the treatment of HIV-1 infection. In our previous work, we have obtained a series of new quinolone-3-carboxylic acids (QCAs) as HIV-1 IN inhibitors and diarylpyrimidines (DAPYs) as RT inhibitors. Based on Morphy's multi-target drug strategy, in this project, we planed to design of a novel series of QCA-DAPY hybrids as HIV-1 dual inhibitors by merging the scaffolds of these two types of inhibitors and docking study of binding mode of these hybrids with RT and IN. The designed hybrids that could adopt right orientation in the binding site of both RT and IN will be synthesized and tested for their HIV-1 IN and RT inhibitory assay, as well as the anti-HIV activity. 3D-QSAR model will also be developed. 1 to 3 target compounds with strong antiviral potency against both HIV-1 wild-type and mutant virus will be further screened for their metabolic stability. It is possible to obtain 1 to 2 new anti-HIV candidates with high anti-HIV potency and metabolic stability in this project. The expected research results would provide a theoretical basis for the development of our own new anti-HIV drugs.