MECHANISTIC EVALUATION OF NEW PLANT-DERIVED COMPOUNDS THAT INHIBIT HIV-1 REVERSE-TRANSCRIPTASE

Swertifrancheside [1], a new flavonone-xanthone glucoside isolated fro m Swertia franchetiana, 1 beta-hydroxyaleuritolic acid 3-p-hydroxybenz oate [2], a triterpene isolated from the roots of Maprounea africana, and protolichesterinic acid [3], an aliphatic alpha-methylene-gamma-la ctone isolated from the lichen Cetraria islandica, were found to be po tent inhibitors of the DNA polymerase activity of human immunodeficien cy virus-1 reverse transcriptase (HIV-1 RT), with 50% inhibitory doses (IC50 values) of 43, 3.7, and 24 mu M, respectively. They were nor cy totoxic with cultured mammalian cells. The kinetic mechanisms by which compounds 1-3 inhibited HIV-1 RT were studied as was their potential to inhibit other nucleic acid polymerases. Swertifrancheside [1] bound to DNA and was shown ro be a competitive inhibitor with respect to te mplate-primer, but a mixed-type competitive inhibitor with respect to TTP. On the other hand, 1 beta-hydroxyaleuritolic acid 3-p-hydroxybenz oate [2] and protolichesterinic acid [3] were mixed-type competitive i nhibitors with respect to template-primer and noncompetitive inhibitor s with respect to TTP. Therefore, the mechanism of action of 1 beta-hy droxyaleuritolic acid 3-p-hydroxybenzoate [2] and protolichesterinic a cid [3] as HIV-1 RT inhibitors involves nonspecific binding to the enz yme at nonsubstrate binding sites, whereas swertifrancheside [1] inhib its enzyme activity by binding to the template-primer.