AIDSWEEKLY Plus, 5 August 1996
Daniel J. DeNoon, Senior Editor

The traditional medicinals do what scientifically designed molecules thus far cannot: inhibit the HIV-1 integrase enzyme.

"These are the most potent small-molecule inhibitors of HIV integrase yet described," said W. Edward Robinson of the University of California, Irvine.

"They actually work to block virus replication in tissue culture, which has been a major problem to date with the integrase inhibitors."

Robinson described the new drugs in a presentation to the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.

The target for the new drugs is HIV integrase, one of three enzymes encoded by the virus. All currently approved anti-HIV drugs attack one of the other two HIV enzymes, reverse transcriptase and protease.

Like its sister enzymes, HIV integrase is essential for viral replication. The enzyme snips the DNA of an infected cell and permits the virus to insert its own genetic code. Host-cell DNA repair mechanisms then mend the cuts, thereby sealing the fate of the cell.

Robinson described the new compounds as dicaffeoylquinic acids.

The natural plant extracts 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 the natural 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."

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