AIDSWEEKLY Plus; Monday, November 23, 1998
Daniel J. DeNoon, Senior Editor
The compound, L-chicoric acid, is a dicaffeoylquinic acid. W.E. Robinson, Jr., of the University of California, Irvine, reported at the 1996 International AIDS Conference that members of this class of compound could inhibit HIV integrase. Integrase is essential for HIV to insert its proviral DNA into the DNA of host cells, a necessary step in viral replication.
Now Robinson has found that L-chicoric acid enhances the in vitro anti-HIV activities of zidovudine (AZT) and a protease inhibitor.
"The addition of L-chicoric acid to either zidovudine or protease inhibitor improved upon the observed anti-HIV activity of either compound alone," Robinson wrote. "When all three drugs were combined, the anti-HIV activity was substantially better than either of the three compounds alone or any combination of two inhibitors."
In the presence of L-chicoric acid doses of AZT and protease inhibitor could be reduced by a third and still retain the same antiretroviral effect.
"These data demonstrate that a first-generation HIV integrase inhibitor, L-chicoric acid, is at least additive in combination with existing multi-drug regimens and suggest that HIV integrase will be an excellent target for combination therapy of HIV infection," Robinson concluded.
Robinson's 1996 report was the first to identify effective inhibitors of HIV integrase.
"These are the most potent small-molecule inhibitors of HIV integrase yet described," he said. "They actually work to block virus replication in tissue culture, which has been a major problem to date with the integrase inhibitors."
The natural plant products inhibited HIV-1 integrase at concentrations ranging from 1 to 7 mg/ml; they exhibited cell toxicity at concentrations ranging from 75 to 225 mg/ml.
"What we think is extremely important about these compounds is that they inhibit the core catalytic domain of integrase," Robinson said.
Robinson and colleagues synthesized more than 30 analogs of these compounds.
"Only four of the synthetic analogs had anti-HIV activity in the range of 2 to 3 mg/ml while the toxicity of the active analogs ranged from 50 to 175 mg/ml," they reported.
Interestingly, the dicaffeoylquinic-acid analogs were also active against feline immunodeficiency virus (FIV) integrase, which is highly divergent from HIV integrase.
"The dicaffeoylquinic acids, therefore, represent a new class of nontoxic antiretroviral compounds active at a unique site (i.e., the level of integration)," Robinson et al. wrote in their presentation abstract. "Thus, HIV integrase offers a novel site for potential anti-HIV therapeutic agents."
The corresponding author for this study is W.E. Robinson, Jr., University of California, Irvine, 92697-4800. Email: <ewrobins@uci.edu>.
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