SYNTHESIS AND ANALYSIS OF HIV INTEGRASE INHIBITORS

点击翻译按钮获取中文摘要

The human immunodeficiency virus (HIV) is the retrovirus associated with the acquired immune deficiency syndrome (AIDS). Like all retroviruses, integration of a complementary DNA copy of the viral RNA genome into a host chromosome is absolutely required for productive and stable infection of cells by HIV. The integration function is carried out by a viral enzyme, integrase, which is an attractive target for the development of novel anti-HIV therapies. To date, the search for HIV integrase inhibitors has been somewhat disappointing: the majority of compounds described that inhibit HIV integrase in biochemical reactions fail to interfere with HIV replication in tissue culture. The dicaffeoylquinic acids and L- chicoric acid represent the first small molecule integrase inhibitors with activity against HIV in tissue culture. These compounds block HIV replication at concentrations ranging from 2 uM to 10uM while the doses that inhibit cellular growth (toxic concentrations) are fully 50-100 times greater. Their activity against HIV integrase in biochemical reactions range from 100nM to approximately 800nM, making them the most potent small molecule integrase inhibitors yet reported. With the identification of these inhibitors, it is now possible to perform in-depth structure activity relationship studies thus making synthesis of more potent and more selective integrase inhibitors not just a goal but a likely possibility. This project would achieve that goal through the following specific aims: 1) Synthesize more potent and less toxic HIV integrase inhibitors. 2) Perform biochemical and mechanistic analyses of existing and new integrase inhibitors. 3) Optimize integrase inhibitors in combination drug therapy. 4) Develop more sensitive and quantitative measures of viral integration within cells. At the least, these studies should offer significant information about the function of HIV integrase and the role of triple therapy targeted against three different HIV enzymes: reverse transcriptase, integrase, and protease. The successful completion of these specific aims may result in a new class of anti-HIV agents that could be evaluated for use in HIV infected individuals both alone and in combination with other anti HIV agents.