Ingenol derivatives are highly potent and selective inhibitors of HIV replication in vitro

Ingenol 3,5,20-triacetate has recently been identified as a highly potent and selective inhibitor of HIV replication in vitro. To evaluate the potential of ingenol derivatives as anti-HIV agents, several ingenol derivatives have been synthesized and investigated for their anti-HIV activities, structure-activity relationships, and possible mechanisms of action. Among the ingenol derivatives, 13-hydroxyingenol-3-(2,3-dimethylbutanoate)-13-dodecanoate (RD4-2138) proved to be a highly potent and selective inhibitor of HIV replication. Its 50% effective concentration for viral replication in MT-4 cells was 0.07-0.5 nM depending on viral strains, including HIV-2. This concentration was approximately 10(5)-fold lower than its cytotoxic threshold. RD4-2138 was also inhibitory to the syncytium formation induced by cocultivation of Molt-4 cells with Molt-4/IIIB cells (Molt-4 cells chronically infected with HIV-1). Some correlation was observed with the ingenol derivatives between their inhibitory effects on HTLV-III, replication and surface CD4 expression in MT-4 cells, suggesting that the mechanism of inhibition is in part attributed to the inhibition of virus adsorption through down-regulation of CD4 molecules in the host cells. However, such correlation was not identified between the inhibition of HTLV-III, and the activation of protein kinase C. Thus, they might have a potential as effective anti-HIV agents when toxicity in vivo could be elucidated.