title: 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 microM. Their activity against reverse transcriptase ranged from 7 microM to greater than 100 microM. Concentrations that inhibited gp120 binding to CD4 exceeded 80 microM. None of the compounds blocked HIV-1 RNase H by 50% at concentrations exceeding 80 microM. 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.
authors.affiliation: Department of Pathology, University of California, Irvine 92697-4800, USA.
authors.forename: B
authors.initials: B
authors.lastname: McDougall
authors.forename: P J
authors.initials: PJ
authors.lastname: King
authors.forename: B W
authors.initials: BW
authors.lastname: Wu
authors.forename: Z
authors.initials: Z
authors.lastname: Hostomsky
authors.forename: M G
authors.initials: MG
authors.lastname: Reinecke
authors.forename: W E
authors.initials: WE
authors.lastname: Robinson
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D002109:Caffeic Acids; D002726:Chlorogenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000187:drug effects; D019427:HIV Integrase / Q000187:drug effects / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D013386:Succinates; D013644:Tartrates / Q000494:pharmacology*
chemical_list: D002109:Caffeic Acids; D002934:Cinnamates; D015699:HIV Envelope Protein gp120; D019428:HIV Integrase Inhibitors; D013386:Succinates; D013644:Tartrates; D002726:Chlorogenic Acid; C100257:cynarine; D019427:HIV Integrase; D054303:HIV Reverse Transcriptase; C100434:3,5-dicaffeoylquinic acid; C100435:chicoric acid