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Molecular Pharmacology, Volume 52, Issue 5, 771-780
Rega Institute for Medical Research (P.C., J.A.E., E.D.C., Z.D.) and Center for Human Genetics (G.R., R.S., G.D.), Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, and Aronex Pharmaceuticals, Inc., The Woodlands, Texas 77380 (R.F.R., J.O.O.).
Oligonucleotides that can form a highly stable intramolecular
four-stranded DNA structure containing two stacked guanosine-quartets (G-quartets) have been reported to inhibit the replication of the human
immunodeficiency virus type 1 (HIV-1) in cell culture. Two possible
mechanisms for the observed antiviral activity have been proposed:
interference with virus adsorption to the cell and/or inhibition of
HIV-1 integrase. We investigated the molecular interaction of
G-quartet-containing oligonucleotides with HIV-1 integrase in
comparison with random oligonucleotides and dextran sulfate. The
prototypical G-quartet-containing oligonucleotide, T30177 (Zintevir),
inhibited the overall integration reaction with an IC50
value of 80 nM. A random oligonucleotide was 10-fold less
potent, but dextran sulfate was more potent, with an IC50 value of 7 nM. We developed novel kinetic assays to dissect
the overall integration reaction in three steps: the formation of the
initial stable complex (ISC), the 3
-processing reaction, and the DNA
strand-transfer step. We then analyzed the kinetics of the ISC
formation and 3-processing. The rate constant determined for the
conversion of ISC into the cleaved product was 0.08 ± 0.01 min
1. T30177 did not inhibit 3-processing or DNA strand
transfer, whereas dextran sulfate inhibited DNA strand transfer to some extent. Binding studies using surface plasmon resonance technology revealed that both T30177 and dextran sulfate were capable of preventing the binding of integrase to specific DNA. We propose a model
in which the interaction of HIV-1 integrase with G-quartets results in
the inhibition of the formation of the ISC between integrase and
substrate DNA. Finally, we selected for an HIV-1 strain that was
resistant to T30177 in cell culture. DNA sequence analysis revealed
mutations in the envelope glycoprotein gp120 but not in the integrase
gene. Although gp120 seems to be the main target for the antiviral
activity in cell culture of G-quartets, the study of their specific
inhibition of HIV-1 integrase may lead to the development of effective
integrase inhibitors.
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