HIV-1 integrase and virus and cell DNAs: complex formation and perturbation by inhibitors of integration.
HIV-1 integrase (IN) catalyzes integration of viral DNA into cell DNA through 3'-processing of viral DNA and strand transfer reactions. To learn on binding of IN to DNAs and IN inhibition we applied spectroscopy (circular dichroism, fluorescence) in a simplified model consisting in a peptide analogue (K156) of alpha4 helix involved in recognition of viral and cell DNA; an oligonucleotide corresponding to the U5' LTR DNA end; and an inhibitor (TB11) of the diketo acid (DKA) family. Results extrapolated to IN show that: the enzyme binds viral DNA with high affinity and specificity, but cell DNA with low affinity and specificity; the affinity of TB11 for IN is high enough to impair the binding of IN to cell DNA, but not to viral DNA. This explains why TB11 is an inhibitor of strand transfer but not of 3'-processing. These results can help in the search of new IN inhibitors.
Hobaika
Z
Z
Laboratoire de Biotechnologies et Pharmacologie génétique Appliquée (LBPA), UMR 8113 du CNRS, Ecole Normale Supérieure de Cachan, 61 Avenue du Président Wilson, 94235, Cachan Cedex, France.
Zargarian
L
L
Maroun
R G
RG
Mauffret
O
O
Burke
T R
TR
Fermandjian
S
S
D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D004279:DNA, Viral / Q000737:chemistry; D019281:Dimerization; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics; D007659:Ketones / Q000737:chemistry; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence; D016662:Virus Integration
D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D007659:Ketones; D010455:Peptides; D004247:DNA; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1