HIV-1逆转录酶/整合酶双重抑制剂DKA-DAPYs的分子设计、合成及抗HIV活性研究

Reverse transcriptase (RT) and integrase (IN) are two indispensable enzymes in the replication cycle of HIV-1. In this work, the diketoacid pharmacophore of IN inhibitors diketoacid analogues (DKAs) was fused into the C-6 position of the pyrimidine ring of RT inhibitors diarylpyrimidines (DAPYs) to get a novel series of diketoacid-substituted diarylpyrimidines (DKA-DAPYs) based on the design philosophy of multi-target drugs. The target molecules were evaluated for their HIV-1 RT and IN inhibitory activities, as well as their activities against wild-type HIV-1, its common mutants and HIV-2. DKA-DAPYs retain the pharmacophoric structure of DAPYs which target HIV-1 RT, and introduce the diketoacid pharmacophore which chelates Mg2+ to target HIV-1 IN, therefore, could dually inhibit HIV-1 RT and IN. DKA-DAPYs, which block both the reverse transcriptation and integration to reduce the surviving chances of HIV-1 mutants, are promising to overcome the widespread drug resistance of the approved anti-HIV drugs.

逆转录酶（RT）和整合酶（IN）是HIV-1复制过程中必不可少的两种酶。本研究基于多靶点药物的设计思路，将IN抑制剂二酮酸类化合物（DKAs）的二酮酸药效团引入到RT抑制剂二芳基嘧啶类化合物（DAPYs）的嘧啶环C-6位，设计得到一类新的衍生物DKA-DAPYs，并测试它们的HIV-1 RT和IN抑制活性，以及它们对HIV-1野生株、常见变异株和HIV-2的抑制活性。DKA-DAPYs既保留了RT抑制剂DAPYs的药效结构，又引入了可与镁离子形成较强配位作用而抑制IN的二酮酸药效团，可起到RT/IN双重抑制作用，连续阻断HIV复制周期中的逆转录和整合两个关键阶段，显著减小HIV-1变异株幸存的机会，有望解决目前RT抑制剂和IN抑制剂普遍存在的耐药性问题。

基于多靶点药物设计思路和分子杂交策略，将二芳基嘧啶类化合物和二酮酸类化合物进行分子杂交，得到新的抗HIV杂合物，并测试了其抗HIV-1和抗HIV-2活性。通过对二芳基嘧啶类化合物进行多轮结构修饰，发现了数个抗HIV活性优秀的新化合物。本项目的实施旨在探索抗HIV药物设计的新思路，期待发现具有我国自主知识产权的结构新颖的新型HIV抑制剂，具有重要的科学意义和广阔的应用前景。本项目共申请了4件中国发明专利，其中一件已获得中国发明专利授权；以第一作者或通讯作者发表SCI论文5篇，包括一篇关于HIV-1逆转录酶/整合酶双重抑制剂合理设计的综述。