Dicaffeoylquinic and Dicaffeoyltartaric Acids Are Selective Inhibitors of Human Immunodeficiency Virus Type 1 Integrase

Abstract

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 dicaffeoyltartaric acids (DCTAs) have potent activity against HIV integrase in vitro and prevent HIV replication in tissue culture. However, their specificity against HIV integrase in cell culture has been questioned. Thus, the ability of the DCQAs and DCTAs to inhibit binding of HIV type 1 (HIV-1) gp120 to CD4 and their activities against HIV-1 reverse transcriptase and HIV RNase H were studied. The DCQAs and DCTAs inhibited HIV-1 integrase at concentrations between 150 and 840 nM. They inhibited HIV replication at concentrations between 2 and 12 μM. Their activity against reverse transcriptase ranged from 7 μM to greater than 100 μM. Concentrations that inhibited gp120 binding to CD4 exceeded 80 μM. None of the compounds blocked HIV-1 RNase H by 50% at concentrations exceeding 80 μM. Furthermore, when the effects of the DCTAs on reverse transcription in acutely infected cells were measured, they were found to have no activity. Therefore, the DCQAs and DCTAs exhibit >10- to >100-fold specificity for HIV integrase, and their activity against integrase in biochemical assays is consistent with their observed anti-HIV activity in tissue culture. Thus, the DCQAs and DCTAs are a potentially important class of HIV inhibitors that act at a site distinct from that of current HIV therapeutic agents.

Antiviral activities of purified compounds from Youngia japonica (L.) DC (Asteraceae, Compositae)

“…In addition, some dicaffeoylquinic acids derived from another plant have been reported to possess anti-HIV activity (Cos et al, 2004). It was suggested that the likely anti-HIV target of dicaffeoylquinic acids could be the HIV-1 integrase (McDougall et al, 1998;Zhu et al, 1999). It was also reported that HIV strains, which were made resistant to the dicaffeic acid derivatives, contained several mutations in its envelope glycoprotein gp 120.…”

Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection

“…50 In follow-up studies, dicaffeoylquinic acids (DCQAs) and dicaffeoyltartaric acids (DCTAs) were found to inhibit HIV-1 integrase at concentrations between 0.15 and 0.84 mM, and HIV replication at concentrations between 2 and 12 mM; no inhibition of gp120 binding to CD4 was noted at concentrations up to 80 mM. 51 Likewise, no inhibition of reverse transcription or RNase H was noted, and it was concluded 51 that the DCQAs and DCTAs act as speci®c integrase inhibitors, and that their activity against integrase is consistent with their observed anti-HIV activity in cell cultures. That the integrase would be an``excellent'' target for combination chemotherapy of HIV infection was further ascertained by combination experiments where L-chicoric acid, the putative integrase inhibitor, was combined with a protease inhibitor (AG1350) and zidovudine.…”

Simultaneous determination of 1,5-dicaffeoylquinic acid and its active metabolites in human plasma by liquid chromatography–tandem mass spectrometry for pharmacokinetic studies

“…DNA integration is carried out by integrase, so HIV-1 integrase represents a key area in developing new antiretroviral therapy [14]. And as no cellular homologue of HIV-1 integrase has been described, this kind of potential inhibitors for HIV-1 integrase could be relatively nontoxic [11,[15][16][17][18][19]. DCQAs have been confirmed to be an effective HIV-1 integrase inhibitor [20] by selectively inhibiting HIV-1 integrase irreversibly toward its conserved amino acid residues in the central core domain of catalysis and preventing HIV-1 replication.…”