Development of Lamellarin Type Anti-HIV Compoundswith a New Mechanism of Action

已知海洋天然产物片螺素α 20-硫酸盐抑制整合酶的IC 50为22 μM，抑制细胞培养物中HIV-1病毒的生长的IC 50为8 μM。MTT法检测片螺素α 20-硫酸酯对HeLa细胞的毒性最小，为274 μM。尽管片螺素α 20-硫酸酯作为新型主要抗HIV-1药物具有很好的前景，但片螺素硫酸酯的构效关系几乎没有研究。在这项研究中，我们已经制备了硫酸化片螺素类似物使用我们的实验室开发的合成策略。构效关系研究表明，五环片层素核心和硫酸基团是抗HIV-1活性所必需的。共聚焦激光显微镜分析和细胞-细胞融合实验表明，硫酸片螺素的抗HIV-1活性是由抑制病毒进入步骤而不是先前指出的整合步骤引起的。

Marine natural product lamellarin α 20-sulfate has been known to inhibit integrase with an IC50 of 22 μM and growth of the HIV-1 virus in cell culture with an IC50 of 8 μM. The MTT assay of lamellarin α 20-sulfate toward HeLa cells displayed the least toxicity of 274 μM. Despite the promising feature of lamellarin α 20-sulfate as a new lead anti-HIV-1 agent, the structure-activity relationships of lamellarin sulfates have scarcely been investigated. In this research, we have prepared sulfated lamellarin analogues using a synthetic strategy developed in our laboratories. The structure-activity relationship study revealed that the pentacyclic lamellarin core and the sulfate group are essential for anti-HIV-1 activity. Confocal laser microscopic analyses and cell-cell fusion experiments suggested that the anti-HIV-1 activity of lamellarin sulfates are caused by inhibition of the virus entry step rather than the previously indicated integration step.