Important note: Information in this article was accurate in January 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, January 25, 1999
Daniel J. DeNoon, Senior Editor
The drugs attack the HIV integrase enzyme. Current drugs target the viral reverse-transcriptase or protease enzymes. Because most integrase inhibitors are not specific for the virus, the new compounds have not been on the fast track for drug development.
But all that may change. Now University of California and Agouron Pharmaceuticals researchers report that the drugs - dicaffeoylquinic acids (DCQAs) and dicaffeoyltartaric acids (DCTAs) - specifically inhibit HIV-1 integrase at concentrations far below their cytotoxic concentrations.
"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," wrote Brenda McDougall, W. Edward Robinson Jr., and colleagues. "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."
McDougall et al. announced their most recent findings in the journal Antimicrobial Agents and Chemotherapy ("Dicaffeoylquinic and Dicaffeoyltartaric Acids Are Selective Inhibitors of Human Immunodeficiency Virus Type 1 Integrase," Antimic Ag Chem, 1999;42(1):140-6).
Compounds with reported anti-HIV activity are 3,5-DCQA; 1- methoxyoxalyl-3,5-DCQA (1-MO-3,5-DCQA); 1,5-DCQA; 3,4-DCQA; 4,5-DCQA; and the DCTA compound L-chicoric acid (L-CCA).
The latter compound, L-chicoric acid, is particularly interesting as it was originally extracted from a Bolivian medicinal plant (see AIDS Weekly Plus, November 23, 1998). Of all the compounds tested in the new studies, this drug shows the most potent inhibition of HIV-1 integrase.
Integrase is essential for HIV to insert its proviral DNA (a cDNA copy of its RNA genome) into the DNA of host cells, a necessary step in viral replication.
"Although mechanistic data within the cell are still lacking, the data strongly support the interpretation that the DCQAs act at the level of HIV integration," McDougall et al. concluded. "Thus the DCQAs mark important lead compounds that can be utilized to study HIV integrase and the mechanism of integration within the cell."
A possible drawback to the therapeutic use of these drugs is that they inhibit HIV only when preincubated with the virus or when added to cell cultures at the same time as virus.
"Why such a preincubation is required is unclear," the authors noted.
Nevertheless, their long-term goal remains the development of a new class of anti-HIV drugs for use in combination with protease and/or reverse-transcriptase inhibitors.
This work was supported by grants from the Public Health Service and the NIAID and by a gift from Agouron Pharmaceuticals Inc.
The corresponding author for this study is W. Edward Robinson Jr., Department of Pathology, D440 Med Sci I, University of California, Irvine, CA 92697-4800. Phone: (714) 824-3431. Fax: (714) 824-2505. Email: <ewrobins@uci.edu>.
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