AEGiS-11IAC: New antiretroviral agents with activity against HIV and FIV integrase.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

New antiretroviral agents with activity against HIV and FIV integrase.

Int Conf AIDS 1996 Jul 7-12; 11:221 (abstract no. Tu.A.264)
Robinson WE, Chow SA, Reinecke MG; Dept. of Pathology, University of California, Irvine, CA, USA. Fax: (714) 824-2505. E-mail: ewrobins@uci.edu.

OBJECTIVE: To identify new anti-HIV agents with activity against integrase.

METHODS: Dicaffeoylquinic acids were purified from plants or analogues were synthesized from simple starting materials. The compounds were tested for inhibition of recombinant HIV-1 integrase purified from Escherichia coli using a simple oligonucleotide-based assay. Compounds identified in this assay as integrase inhibitors were tested in vitro for both cell toxicity and anti-HIV activity in tissue culture using either T cell lines, monocyte/macrophage-like cell lines, or peripheral blood mononuclear cells.

RESULTS: Fractionation of Bolivian medicinal plant extracts yielded several new anti-HIV compounds with activity against HIV integrase at concentrations of less than 1 microgram/ml. All of the compounds were dicaffeoylquinic acids. Cell toxicity of the natural products ranged from a low of 75 micrograms/ml to a high of 225 micrograms/ml. The anti-HIV activity of these compounds ranged from a high of 7 micrograms/ml to a low of 1 microgram/ml. Over thirty synthetic analogues of these compounds were synthesized and tested for anti-HIV activity. Only four of the synthetic analogues had anti-HIV activity in the range of 2-3 micrograms/ml while the toxicity of the active analogues ranged from 50-175 micrograms/ml. All of the active compounds were tested for activity against FIV integrase in vitro. The dicaffeoylquinic acids inhibited both FIV integrase and HIV integrase in vitro.

CONCLUSIONS: These data suggest that the dicaffeoylquinic acids and some analogues can inhibit HIV integrase in vitro as well as HIV infection of susceptible cell lines. Furthermore, active compounds can inhibit the genetically divergent integrase from FIV. The dicaffeoylquinic acids, therefore, represent a new class of nontoxic anti-retroviral compounds active at a unique enzymatic site (i.e. the level of integration). Thus, HIV integrase offers a novel site for potential anti-HIV therapeutic agents.

Keywords: AEGIS, Integrase, HIV Integrase, HIV Integrase Inhibitors, Antiviral Agents, Anti-HIV Agents, Integrase Inhibitors, HIV Protease Inhibitors, Acquired Immunodeficiency Syndrome, Cell Line, HIV Infections, T-Lymphocytes, Bolivia, South America, In Vitro, ICA11

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TuA264