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

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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.