新型香豆素类抗HIV-RT/PR的活性及其构效关系研究

Coumarin derivatives has been demonstrated in our lab to inhibit the activity of human immunodeficiency virus type 1(HIV-1) reverse trancriptase(RT) and HIV-1 protease(PR) in cell free system. It also show inhibition effects on HIV replication in cell culture. Based on the chinese traditional pharmacological characteristic and protein three dimension computer aided design, analoges of tetracyclic dipyranocoumarin were synthesized from natural leading compounds, including two natural products Cordatolide A and Inophyllum B. We studied the relationship of antiviral effects and chemical structures via HIV-1 PR/RT enzyme models and tissue culture model system. 65 compounds were designed and tested. According to our experiment data, V9722, which is an analog of calanolide A, showed significant inhibition effect on HIV-1 RT with IC50 of HIV-1 RT of wild strain and resistant strain of 3.17μM and 0.114μM, respectively. In cell culture V9722 was demonstrated the anti-HIV-1 replication activities in various cell cultures against different HIV-1 wild strains and resistant strains. It also showed synergic anti-HIV-1 activities with AZT, indinavir and T-20. Compounds V0201 targated against HIV-1 PR/RT with IC50 of 3.16μM and 0.78μM, respectively. V0201 is a highly active inhibitor with IC50 0.037μM in cell culture. These experiment data indicate that our both design strategies are successful to obtain new anti-HIV agents in which V0201 is a novel structure and maybe a new leading compound. We concluded these new compounds are worth to develop new anti-HIV drugs in the future.

在既往研究中发现不同香豆素衍生物具有抑制HIV-1 RT 或HIV-1 PR活性，且在细胞培养内显示抑制HIV复制作用。本课题根据国内传统药学特点，以天然产物为先导物，结合蛋酌溉峁辜扑慊ㄖ杓疲铣扇芳八幕匪拎愣顾匮苌铮礁鎏烊徊顲ordatolide A 及Inophyllum B。以HIV RT及HIV PR为靶点，进行构效关系研究，以期为发展夜笻IV药物提供有效化合物。