Mechanistic evaluation of new plant-derived compounds that inhibit HIV-1 reverse transcriptase.
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.
Pengsuparp
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T
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago 60612, USA.
Cai
L
L
Constant
H
H
Fong
H H
HH
Lin
L Z
LZ
Kinghorn
A D
AD
Pezzuto
J M
JM
Cordell
G A
GA
Ingolfsdóttir
K
K
Wagner
H
H
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D019384:Nucleic Acid Synthesis Inhibitors; D010946:Plants, Medicinal / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013698:Templates, Genetic; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D014966:Xanthenes / Q000494:pharmacology*; D044004:Xanthones; D015215:Zidovudine / Q000494:pharmacology
C095782:1-hydroxyaleuritolic acid 3-(4-hydroxybenzoate); D005419:Flavonoids; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; D014315:Triterpenes; D014966:Xanthenes; D044004:Xanthones; C095781:protolichesterinic acid; C087101:swertifrancheside; D012710:Serum Albumin, Bovine; D015215:Zidovudine; D004247:DNA; D012321:DNA-Directed RNA Polymerases; D015107:4-Butyrolactone