DICAFFEOYLQUINIC AND DICAFFEOYLTARTARIC ACIDS ARE SELECTIVE INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INTEGRASE

Current pharmacological agents for human immunodeficiency virus (HIV) infection include drugs targeted against HIV reverse transcriptase and HIV protease. An understudied therapeutic target is HIV integrase, an essential enzyme that mediates integration of the HIV genome into the host chromosome. The dicaffeoylquinic acids (DCQAs) and the dicaffeoy ltartaric acids (DCTAs) have potent activity against HIV integrase in vitro and prevent HIV replication in tissue culture. However, their sp ecificity against HIV integrase in cell culture has been questioned. T hus, the ability of the DCQAs and DCTAs to inhibit binding of HIV type 1 (HIV-1) gp120 to CD4 and their activities against HIV-I reverse tra nscriptase and HIV RNase H were studied. The DCQAs and DCTAs inhibited HIV-1 integrase at concentrations between 150 and 840 nM. They inhibi ted HIV replication at concentrations between 2 and 12 mu M. Their act ivity against reverse transcriptase ranged from 7 mu M to greater than 100 mu M. Concentrations that inhibited gp120 binding to CD4 exceeded 80 mu M. None of the compounds blocked HIV-1 RNase H by 50% at concen trations exceeding 80 mu M. Furthermore, when the effects of the DCTAs on reverse transcription in acutely infected cells were measured, the y were found to have no activity. Therefore, the DCQAs and DCTAs exhib it >10- to >100-fold specificity for HIV integrase, and their activity against integrase in biochemical assays is consistent with their obse rved anti-HIV activity in tissue culture. Thus, the DCQAs and DCTAs ar e a potentially important class of HIV inhibitors that act at a site d istinct from that of current HIV therapeutic agents.