Lamellarin alpha 20-sulfate, an inhibitor of HIV-1 integrase active against HTV-1 virus in cell culture

HIV-1 integrase is an attractive target for anti-retroviral chemotherapy, b ut to date no clinically useful inhibitors have been developed. We have scr eened diverse marine natural products for compounds active against integras e in vitro and found a series of ascidian alkaloids, the lamellarins, that show selective inhibition. A new member of the family named lamellarin alph a 20-sulfate (1), the structure of which was determined from spectroscopic data, displayed the most favorable therapeutic index. The site of action of lamellarin alpha 20-sulfate on the integrase protein was mapped by testing activity against deletion mutants of integrase. Inhibition of isolated cat alytic domain was detectable though weaker than inhibition of full length i ntegrase; possibly lamellarin alpha 20-sulfate binds a site composed of mul tiple integrase domains. Lamellarin alpha 20-sulfate also inhibited integra tion in vitro by authentic HIV-1 replication intermediates isolated from in fected cells. Lamellarin alpha 20-sulfate was tested against wild type HIV using the MAGI indicator cell assay and found to inhibit early steps of HIV replication. To clarify the inhibitor target, we tested inhibition against an HIV-based retroviral vector bearing a different viral envelope. Inhibit ion was observed, indicating that the HIV envelope cannot be the sole targe t of lamellarin alpha 20-sulfate in cell culture. In addition, these single round tests rule out action against viral assembly or budding. These findi ngs provide a new class of compounds for potential development of clinicall y useful integrase inhibitors.