Phosphorothioate analogues of oligodeoxyribonucleotide: Synthesis and activity as inhibitors of replication of human immunodeficiency virus

Kim, Sang-Gug; Suzuki, Yoshikazu; Nakashima, Hideki; Yamamoto, Naoki; Takaku, Hiroshi

doi:10.1016/0006-291x(91)91759-6

Cited by 28 publications

(20 citation statements)

References 15 publications

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“…In particular, the whole phosphorothioate-diester oligomer having Rp or Sp had a marked affect on triplex formation [6]. Thus thio-DNAs (R.p or Sp) are more resistant to n uclease than the parent polymers [15,16]. Therefore, they may be useful as 'antisense' compounds for inhibiting viral replication or transcription from specific genes.…”

Section: Resultsmentioning

confidence: 99%

“…Oligomers were prepared with a synthesizer uain 8 oar new phosphite approach and were purified by reverse-phase chromatol~ra-phy using published procedures [16]. The presence of P-S bond~ in phosphorothioates was confirmed using ~'P-NMR spectroscopy.…”

Section: Methodsmentioning

confidence: 99%

“…Nucleaseresistant phosphorothioate oligomers were more effective antisense inhibitors of HIV, and would be more effective for duplex formation, and retention of the water solubility of charged phosphates (cellular uptake via receptor) [13][14][15][16]. To determine the effect of the phosphorothioate substitution on the conformation of triplex DNA, we chose oligomers having phosphorothioate internucleotidie bonds of a mixture of diastereoisomers or one of the two stereoisomers (either Rp or Sp).…”

Section: Introductionmentioning

confidence: 99%

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The influence of oligodeoxyribonucleotide phosphorothioate pyrimidine strands on triplex formation

et al. 1992

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Analogues of the homopyrimidine oiigonucleotide dT,s that contained phosphorothioat¢ bonds of a mixture ofdiastereoisomers or one of tile two stereoisomers (either Rp or Sp) were synthesized. The analogues were mixed under eondition~ conducive to the formation of tripl¢.-.atranded assemblies. The mixtures were characterized by their thermal stabilities (7"1,, values), CD spectra, and gel electropltoresis pattern. The 34-met duplexes containing 15 central purines on one strand attd 15 complementary pyrimidines on the other strand gave no detectable triple helix upon combination with dTt~S~. On the other hand, 34-bp duplexes with dT~sS,, having Rp or Sp, formed triple helix~. This suggests that a sterie factor plays an important role in triple helix formation.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The influence of oligodeoxyribonucleotide phosphorothioate pyrimidine strands on triplex formation

et al. 1992

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“…1). Native (phosphodiester) antisense oligonucleotides have generally been reported to have little (2) or no inhibitory effect against HIV-1 in culture (3)(4)(5) because they are rapidly degraded in culture medium (6)(7)(8). Two approaches exist to circumvent this degradation.…”

Section: Introductionmentioning

confidence: 99%

Antisense oligonucleotides in solution or encapsulated in immunoliposomes inhibit replication of HIV-1 by several different mechanisms

Zelphati¹,

Imbach²,

Signoret³

et al. 1994

Nucl Acids Res

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Phosphodiester and phosphorothioate oligonucleotides in a and , configurations directed against the initiation codon region of the HIV-1 rev gene were evaluated for their ability to inhibit HIV-1 replication in acutely and chronically infected human CEM cells. Encapsulation in antibody-targeted liposomes (immunoliposomes) permitted intracellular delivery and distinction between oligonucleotide-mediated inhibition of viral entry and intracellular effects on viral RNA. Our results are consistent with four mechanisms of antiviral activity for these antisense oligonucleotides: (i) interference with virus-mediated cell fusion by free but not liposome-encapsulated phosphorothioate oligonucleotides of any sequence; (ii) interference with reverse transcription in a sequence non-specific manner by phosphorothioate oligonucleotides in a and a configurations; (iii) interference with viral reverse transcription in a sequence-specific and RNase-H-independent manner by a and (3 phosphodiester oligonucleotides; (iv) interference with viral mRNA in a sequence-specific and RNase-H-dependent manner by 0-phosphorothioate oligonucleotides.

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“…In previous studies, we and others have shown that phosphodiester oligonucleotides free in solution were unable to inhibit HIV replication (up to a concentration of 50 /zM) because their degradation by extracellular nucleases is rapid and their uptake relatively poor (Matsukura et al, 1987;Kim et al, 1991;Kinchington et al, 1992;Zelphati et al, 1993). To protect oligonucleotides from nuclease action and to concentrate them at the cell surface we encapsulated oligonucleotides or incorporated oligonucleotides coupled to cholesterol in liposomes and evaluated their antiviral activity.…”

Section: Antiviral Effects Of Oligonucleotides Encapsulated or Incorpmentioning

confidence: 99%

Synthesis and anti-HIV activity of thiocholesteryl-coupled phosphodiester antisense oligonucleotides incorporated into immunoliposomes

1994

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Encapsulation of oligonucleotides in antibody-targeted liposomes (immunoliposomes) which bind to target cells permits intracellular delivery of the oligonucleotides. This approach circumvents problems of extracellular degradation by nucleases and poor membrane permeability which free phosphodiester oligonucleotides are subject to, but leaves unresolved the inefficiency of encapsulation of oligonucleotides in liposomes. We have coupled oligonucleotides to cholesterol via a reversible disulfide bond. This modification of oligonucleotides improved their association with immunoliposomes by a factor of about 10 in comparison to unmodified oligonucleotides. The presence of cholesteryl-modified oligonucleotides incorporated in the bilayer of liposomes did not interfere with the coupling of the targeting protein to the liposome surface. Free or cholesterol coupled oligonucleotides associated with liposomes and directed against the tat gene of HIV-1 were tested for inhibition of HIV-1 proliferation in acutely infected cells. We demonstrate that the cholesteryl-modified as well as unmodified oligonucleotides acquire the target specificity of the antibody on the liposome. Their antiviral activity when delivered into cells is sequence-specific. The activity of these modified or unmodified oligonucleotides to inhibit the replication of HIV was the same on an equimolar basis (ECs0 around 0.1 /~M). Cholesterol coupled oligonucleotides thus offer increased liposome association without loss of antiviral activity.

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Phosphorothioate analogues of oligodeoxyribonucleotide: Synthesis and activity as inhibitors of replication of human immunodeficiency virus

Cited by 28 publications

References 15 publications

The influence of oligodeoxyribonucleotide phosphorothioate pyrimidine strands on triplex formation

The influence of oligodeoxyribonucleotide phosphorothioate pyrimidine strands on triplex formation

Antisense oligonucleotides in solution or encapsulated in immunoliposomes inhibit replication of HIV-1 by several different mechanisms

Synthesis and anti-HIV activity of thiocholesteryl-coupled phosphodiester antisense oligonucleotides incorporated into immunoliposomes

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