Branched oligonucleotide‐intercalator conjugate forming a parallel stranded structure inhibits HIV‐1 integrase

Brodin, Priscille; Pinskaya, Marina; Волков, Е. М.; Романова, Е. А.; Leh, Hervé; Auclair, Christian; Mouscadet, Jean‐François; Gottikh, Marina

doi:10.1016/s0014-5793(99)01350-2

Cited by 10 publications

(4 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Development of these assays has made possible the identification of several classes of integrase inhibitors, among them nucleotides and oligonucleotides (for a recent review, see ref 9). With regard to the oligonucleotides, most studies focused on structure-forming oligonucleotides such as tetradforming oligonucleotides (10)(11)(12), structured branched compounds (13), and triplex-forming oligonucleotides (14, † This work was supported by funds from INTAS Grant 96-1216, from Russian Foundation for Basic Research Grant 02-04-48797, from the Agence Nationale de Recherche sur le Sida (ANRS), and from SIDACTION. P.B.…”

mentioning

confidence: 99%

Disruption of HIV-1 Integrase−DNA Complexes by Short 6-Oxocytosine-Containing Oligonucleotides^,

et al. 2002

Self Cite

View full text Add to dashboard Cite

We recently found that oligonucleotides containing the 6-oxocytosine heterocyclic base are efficient inhibitors of the HIV-1 integrase in vitro [Brodin, P., et al. (2001) Nucleosides Nucleotides Nucleic Acids 20, 481-486]. In this report, we demonstrate that the inhibition arises from a noncompetitive mechanism in which the modified oligonucleotide attacks the integrase-DNA complex, leading to its active disruption. This conclusion is based on the following results. First, despite the fact that the respective affinities of a 6-oxocytosine-containing oligonucleotide and of its nonmodified counterpart for integrase were identical, only the modified compound inhibited the enzyme activities. Second, DNA binding and UV cross-linking assays indicated that the 6-oxocytosine-containing oligonucleotide prevented the formation of a stable integrase-DNA complex. Third, the kinetics of the dissociation of the integrase-DNA complex were dramatically accelerated in the presence of the modified ODN, whereas the nonmodified counterpart did not influence the dissociation. This mechanism was supported by the ability of the 6-oxocytosine-containing oligonucleotide to inhibit the strand transfer activity of HIV-1 preintegration complexes in vitro. Disruption of integrase-DNA complexes by 6-oxocytosine-containing oligonucleotides constitutes an original mechanism of integration inhibition, therefore suggesting a strategy for searching for inhibitors of the HIV-1 preintegration complexes.

show abstract

mentioning

confidence: 99%

Disruption of HIV-1 Integrase−DNA Complexes by Short 6-Oxocytosine-Containing Oligonucleotides^,

et al. 2002

Self Cite

View full text Add to dashboard Cite

show abstract

“…Compounds that specifically bind to the extremities of the viral cDNA could act as antagonists of the binding of IN or the PIC to the viral DNA. DNA intercalating compounds belong to this class but, without sequence specificity, they are too toxic limiting their application in HAART [53][54][55]. As a consequence, sequence specificity of DNA binding inhibitors (DBINs) is an indispensable prerequisite for antiviral drug development.…”

Section: Dna Binding Inhibitorsmentioning

confidence: 99%

Targeting Integration beyond Strand Transfer: Development of Second‐Generation HIV Integrase Inhibitors

Voet

Maeyer

Christ

et al. 2011

Antiviral Drug Strategies

View full text Add to dashboard Cite

“…In order to develop selective HIV-1 integrase inhibitors, some groups have developed an elegant strategy using DNA-binding proteins combined with ODN that have the propensity to form specific DNA triple-helix. Coupling of oxazolopyridocarbazole (OPC) or acridine (ACR) to the 5′ end of linear or branched ODN containing the polypurine sequences located within the HIV-1 LTR termini allowed inhibition of purified HIV-1 integrase with IC 50 values of 0.5 to 1.5 µM [177][178][179][180]. The conserved AT-rich sequence located at the end of the viral LTR was also targeted by the minor groove-binding ligands netropsin, lexitropsin and bisdistamycine [154,175].…”

Section: Dna Intercalatorsmentioning

confidence: 99%

Targeting HIV-1 integrase

Sayasith

Sauvé

Yelle³

2001

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

Human immunodeficiency virus Type 1 (HIV-1) integrase is an essential enzyme for the obligatory integration of the viral DNA into the infected cell chromosome. As no cellular homologue of HIV integrase has been identified, this unique HIV-1 enzyme is an attractive target for the development of new therapeutics. Treatment of HIV-1 infection and AIDS currently consists of the use of combinations of HIV-1 inhibitors directed against reverse transcriptase (RT) and protease. However, their numerous side effects and the rapid emergence of drug-resistant variants limit greatly their use in many AIDS patients. In principle, inhibitors of the HIV-1 integrase should be relatively non-toxic and provide additional benefits for AIDS chemotherapy. There have been many major advances in our understanding of the molecular mechanism of the integration reaction, although some critical aspects remain obscure. Several classes of compounds have been screened and further scrutinised for their inhibitory properties against the HIV integrase; however, there are currently no useful inhibitors available clinically for the treatment of AIDS patients. This review describes the current knowledge of the biological functions of the HIV-1 integrase and reports the major classes of integrase inhibitors identified to date.

show abstract

Branched oligonucleotide‐intercalator conjugate forming a parallel stranded structure inhibits HIV‐1 integrase

Cited by 10 publications

References 26 publications

Disruption of HIV-1 Integrase−DNA Complexes by Short 6-Oxocytosine-Containing Oligonucleotides^,

Disruption of HIV-1 Integrase−DNA Complexes by Short 6-Oxocytosine-Containing Oligonucleotides^,

Targeting Integration beyond Strand Transfer: Development of Second‐Generation HIV Integrase Inhibitors

Targeting HIV-1 integrase

Contact Info

Product

Resources

About

Branched oligonucleotide‐intercalator conjugate forming a parallel stranded structure inhibits HIV‐1 integrase

Cited by 10 publications

References 26 publications

Disruption of HIV-1 Integrase−DNA Complexes by Short 6-Oxocytosine-Containing Oligonucleotides,

Disruption of HIV-1 Integrase−DNA Complexes by Short 6-Oxocytosine-Containing Oligonucleotides,

Targeting Integration beyond Strand Transfer: Development of Second‐Generation HIV Integrase Inhibitors

Targeting HIV-1 integrase

Contact Info

Product

Resources

About

Disruption of HIV-1 Integrase−DNA Complexes by Short 6-Oxocytosine-Containing Oligonucleotides^,

Disruption of HIV-1 Integrase−DNA Complexes by Short 6-Oxocytosine-Containing Oligonucleotides^,