Triple Helix Formation with Short Oligonucleotide-Intercalator Conjugates Matching the HIV-1 U3 LTR End Sequence

Mouscadet, Jean François; Ketterlé, Christophe; Goulaouic, Hélène; Carteau, Sandrine; Subra, Frédéric; Bret, Marc Le; Auclair, Christian

doi:10.1021/bi00180a011

Cited by 62 publications

(33 citation statements)

References 50 publications

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“…Therefore, stabilization of the pyrimidine motif triplex at physiological pH is of great importance in improving its therapeutic potential to artificially control gene expression in vivo. Numerous efforts such as the replacement of cytosine bases in a homopyrimidine TFO with 5-methylcytosine (7,(11)(12)(13) or other chemically modified bases (14 -18), the conjugation of different DNA intercalators to TFO (19,20), and the use of polyamines such as spermine or spermidine as triplex stabilizers (21) have been made to improve the stability of the pyrimidine motif triplex at physiological pH.…”

mentioning

confidence: 99%

2′-O,4′-C-Methylene Bridged Nucleic Acid Modification Promotes Pyrimidine Motif Triplex DNA Formation at Physiological pH

Torigoe¹,

Hari²,

Sekiguchi³

et al. 2001

Journal of Biological Chemistry

135

126

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mentioning

confidence: 99%

2′-O,4′-C-Methylene Bridged Nucleic Acid Modification Promotes Pyrimidine Motif Triplex DNA Formation at Physiological pH

Torigoe¹,

Hari²,

Sekiguchi³

et al. 2001

Journal of Biological Chemistry

135

126

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“…Stabilization of the pyrimidine motif triplex at physiological pH is therefore of great importance in improving its therapeutic potential. Numerous efforts such as the replacement of cytosine bases in a homopyrimidine TFO with 5-methylcytosine (9, 11-13) or other chemically modified bases (14 -18), the conjugation of different DNA intercalators to TFO (19,20) and/or the use of polyamines such as spermine or spermidine as triplex stabilizers (21) have been made to improve the stability of the pyrimidine motif triplex at physiological pH. However, in some cases, modification strategies lessened the overall binding affinity of the TFO or increased its nonspecific interaction with DNA (2, 18).…”

mentioning

confidence: 99%

Poly(l-lysine)-graft-dextran Copolymer Promotes Pyrimidine Motif Triplex DNA Formation at Physiological pH

Torigoe¹,

Ferdous

Watanabe

et al. 1999

Journal of Biological Chemistry

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Extreme instability of pyrimidine motif triplex DNA at physiological pH severely limits its use for artificial control of gene expression in vivo. Stabilization of the pyrimidine motif triplex at physiological pH is therefore of great importance in improving its therapeutic potential. To this end, isothermal titration calorimetry interaction analysis system and electrophoretic mobility shift assay have been used to explore the thermodynamic and kinetic effects of our previously reported triplex stabilizer, poly (L-lysine)-graft-dextran (PLL-g-Dex) copolymer, on pyrimidine motif triplex formation at physiological pH. Both the thermodynamic and kinetic analyses have clearly indicated that in the presence of the PLL-g-Dex copolymer, the binding constant of the pyrimidine motif triplex formation at physiological pH was about 100 times higher than that observed without any triplex stabilizer. Of importance, the triplex-promoting efficiency of the copolymer was more than 20 times higher than that of physiological concentrations of spermine, a putative intracellular triplex stabilizer. Kinetic data have also demonstrated that the observed copolymer-mediated promotion of the triplex formation at physiological pH resulted from the considerable increase in the association rate constant rather than the decrease in the dissociation rate constant. Our results certainly support the idea that the PLL-g-Dex copolymer could be a key material and may eventually lead to progress in therapeutic applications of the antigene strategy in vivo.In recent years, triplex DNA has attracted considerable interest because of its possible biological functions in vivo and its wide variety of potential applications, such as regulation of gene expression, site-specific cleavage of duplex DNA, mapping of genomic DNA, and gene-targeted mutagenesis (1-3). A triplex is usually formed through the sequence-specific interaction of a single-stranded homopurine or homopyrimidine triplex-forming oligonucleotide (TFO) 1 with the major groove of the homopurine-homopyrimidine stretch in duplex DNA (1-5).In the purine motif triplex, a homopurine TFO binds antiparallel to the homopurine strand of the target duplex by reverse Hoogsteen hydrogen bonding to form A⅐A:T (or T⅐A:T) and G⅐G:C triplets (1-5). On the other hand, in the pyrimidine motif triplex, a homopyrimidine TFO binds parallel to the homopurine strand of the target duplex by Hoogsteen hydrogen bonding to form T⅐A:T and C ϩ ⅐G:C triplets (1-5). Because the cytosine bases in a homopyrimidine TFO are to be protonated to bind with the guanine bases of the G:C duplex, the formation of the pyrimidine motif triplex needs an acidic pH condition and is thus extremely unstable at physiological pH (6 -10). The extreme instability of the pyrimidine motif triplex at physiological pH severely limits its use for artificial control of gene expression in vivo. Stabilization of the pyrimidine motif triplex at physiological pH is therefore of great importance in improving its therapeutic potential. Numerous efforts suc...

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“…For the pyrimidine conjugate, there was an inhibitory effect of U3 insertion (IC 50 y100 nM). The purine conjugate was more inhibitory with an IC 50 of y50 nM [28,29]. Complicating factors of these compounds would include intracellular permeability as well as the high mutation rate of HIV that may result in substitutions in some of the bases in the LTR.…”

Section: Oligonucleotide Inhibitorsmentioning

confidence: 99%

“…These bioconjugates would interact with viral DNA through triplex formation [28] and thus may block the catalytic functions of integrase and also provide sequence-specific inhibition of the U3 integration process [28]. Several such oligonucleotideintercalator conjugates have shown inhibitory activity toward HIV integrase [28,29]. These triplex forming oligonucleotide conjugates are composed of a 7-mer oligonucleotide, matching the polypurine/polypyrimidine sequence located in the HIV-1 U3 LTR end region, bonded through a pentamethylene bridge to an intercalating oxalopyridocarbazole (OPC) chromophore ( Figure 6, compounds 5 and 6) [28,29].…”

Section: Oligonucleotide Inhibitorsmentioning

confidence: 99%

“…Several such oligonucleotideintercalator conjugates have shown inhibitory activity toward HIV integrase [28,29]. These triplex forming oligonucleotide conjugates are composed of a 7-mer oligonucleotide, matching the polypurine/polypyrimidine sequence located in the HIV-1 U3 LTR end region, bonded through a pentamethylene bridge to an intercalating oxalopyridocarbazole (OPC) chromophore ( Figure 6, compounds 5 and 6) [28,29]. For the pyrimidine conjugate, there was an inhibitory effect of U3 insertion (IC 50 y100 nM).…”

Section: Oligonucleotide Inhibitorsmentioning

confidence: 99%

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HIV integrase as a target for antiviral chemotherapy

Nair

2002

Reviews in Medical Virology

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One of the three key enzymes encoded by the pol gene of HIV is a M(r) 32 000 protein called HIV integrase. This viral enzyme is involved in the integration of HIV DNA into host chromosomal DNA. There appears to be no functional equivalent of the enzyme in human cells. The biochemical mechanism of integration of HIV DNA into the host cell genome involves a carefully defined sequence of DNA tailoring (3'-processing) and coupling (joining or integration) reactions. In spite of some effort in this area targeted at the discovery of therapeutically useful inhibitors of this viral enzyme, there are no drugs for HIV/AIDS in clinical use where the mechanism of action is inhibition of HIV integrase. Thus, new knowledge on inhibitors of this enzyme is of critical importance in the anti-HIV drug discovery area. The focus of this review will be on several classes of compounds, including nucleotides, dinucleotides, oligonucleotides and miscellaneous small molecules such as heterocyclic systems, natural products, diketo acids and sulfones, that have been discovered as inhibitors of HIV integrase. Special emphasis in the review will be placed on discoveries from my laboratory on HIV integrase inhibitors that are non-natural, nuclease-resistant dinucleotides. Comments on future directions and the prospects for developing integrase inhibitors as therapeutic antiviral agents are discussed.

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Triple Helix Formation with Short Oligonucleotide-Intercalator Conjugates Matching the HIV-1 U3 LTR End Sequence

Cited by 62 publications

References 50 publications

2′-O,4′-C-Methylene Bridged Nucleic Acid Modification Promotes Pyrimidine Motif Triplex DNA Formation at Physiological pH

2′-O,4′-C-Methylene Bridged Nucleic Acid Modification Promotes Pyrimidine Motif Triplex DNA Formation at Physiological pH

Poly(l-lysine)-graft-dextran Copolymer Promotes Pyrimidine Motif Triplex DNA Formation at Physiological pH

HIV integrase as a target for antiviral chemotherapy

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