Mechanistic Evaluation of New Plant-Derived Compounds That Inhibit HIV-1 Reverse Transcriptase

Abstract

Swertifrancheside [1], a new flavonone-xanthone glucoside isolated from Swertia franchetiana, 1 beta-hydroxyaleuritolic acid 3-p-hydroxybenzoate [2], a triterpene isolated from the roots of Maprounea africana, and protolichesterinic acid [3], an aliphatic alpha-methylene-gamma-lactone isolated from the lichen Cetraria islandica, were found to be potent inhibitors of the DNA polymerase activity of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT), with 50% inhibitory doses (IC50 values) of 43, 3.7, and 24 microM, respectively. They were not cytotoxic 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 to be a competitive inhibitor with respect to template-primer, but a mixed-type competitive inhibitor with respect to TTP. On the other hand, 1 beta-hydroxyaleuritolic acid 3-p-hydroxybenzoate [2] and protolichesterinic acid [3] were mixed-type competitive inhibitors with respect to template-primer and noncompetitive inhibitors with respect to TTP. Therefore, the mechanism of action of 1 beta-hydroxyaleuritolic acid 3-p-hydroxybenzoate [2] and protolichesterinic acid [3] as HIV-1 RT inhibitors involves nonspecific binding to the enzyme at nonsubstrate binding sites, whereas swertifrancheside [1] inhibits enzyme activity by binding to the template-primer.

Naturally Occurring Xanthones: Chemistry and Biology

“…S. hookeri extract is used in the treatment of microbial infections and as a mood elevator [97]. Swertifrancheside isolated from S. franchetiana was found to be potent inhibitor of the DNA polymerase activity of human immunodeficiency virus-1 reverse transcriptase [98]. Naturally occurring xanthones have emerged as an important class of organic compounds in view of their remarkable pharmacological and other biological activities.…”

Chemotaxonomy and pharmacology of Gentianaceae

“…Finally, swertifrancheside was found to be a potent inhibitor of the DNA polymerase activity of HIV-1 reverse transcriptase (Pengsuparp et al, 1995), and five tetrahydroxyxanthones isolated from Tripterospermum lanceolatum were shown to have a strong inhibitory effect on the activity of Moloney murine leukemia virus reverse transcriptase (Chang et al, 1992). The tetrahydroxyxanthones also inhibited angiotensin-1-converting-enzyme (ACE) activity in a dose-dependent manner (Chen et al, 1992).…”

Preclinical anti-HSV-1 activity of aqueous and methanol extracts of Kenya grown pyrethrum (Chrysanthemum cinerariaefolium)

“…These secondary metabolites from other plants have shown bioactivity, as it is indicated elsewhere were flavonoids (Pengsuparp et al, 1995) and alkaloids (McMahon et al, 1995) contain anti-HSV activity. According to the study done by Sassi et al (2008), C. trifurcatum grown elsewhere exhibited in vitro anti-HSV activity, also, Stanberry et al (1986) indicated, Pyrerhrins the active insecticide from C. cinerariaefolim exhibited in vitro anti HSV activity.…”