Phosphorothioate analogs of oligodeoxynucleotides: inhibitors of replication and cytopathic effects of human immunodeficiency virus.

Matsukura, Makoto; Shinozuka, Kazuo; Zon, Gerald; Mitsuya, Hiroaki; Reitz, Marvin S.; Cohen, Jack S.; Broder, Samuel

doi:10.1073/pnas.84.21.7706

Cited by 477 publications

(234 citation statements)

References 22 publications

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“…57 The oligomers were purified as described previously. 58 The oligonucleotide sequence for JNK1 sense (5' ± 3'): ATG TGC ATC GGT GAC and for JNK1 antisense (5' ± 3'): GTC ACC GAT GCA CAT.…”

Section: Sense and Antisense Oligonucleotidesmentioning

confidence: 99%

IL-2 deprivation triggers apoptosis which is mediated by c-Jun N-terminal kinase 1 activation and prevented by Bcl-2

et al. 1999

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A variety of environmental stresses, as well as inflammatory cytokines, induce activation of c-Jun N-terminal kinases. We describe here that IL-2 deprivation-induced apoptosis in TS1ab cells does not modify c-Jun protein levels and correlates Bcl-2 downregulation and an increase in JNK1, but not JNK2, activity directly related to the induction of apoptosis. Indeed, downregulation of JNK1 expression using antisense oligonucleotides inhibits apoptosis induced by IL-2 withdrawal. Overexpression of Bcl-2 promotes cell survival and blocks JNK1 activation as well as apoptosis caused by IL-2 deprivation. This suggests that inhibition of the JNK1 signaling pathway may be a mechanism through which Bcl-2 promotes cell survival and prevents apoptosis triggered by growth factor withdrawal.

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Section: Sense and Antisense Oligonucleotidesmentioning

confidence: 99%

IL-2 deprivation triggers apoptosis which is mediated by c-Jun N-terminal kinase 1 activation and prevented by Bcl-2

et al. 1999

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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%

“…These include phosphorothioate oligonucleotides and oligonucleotides with the sugar moiety oriented in the at configuration. Phosphorothioate oligonucleotides have been shown to inhibit the replication of HIV-1 in vitro by both sequence-non-specific (3,5,10,11) and specific processes (12)(13)(14)(15)(16), depending on the type of infection. In acutely infected cells, phosphorothioate oligonucleotides acted in a sequence-non-specific fashion probably by inhibition of viral binding and fusion (17,18) and/or viral reverse transcriptase (RT) (19,20).…”

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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“…Presumably, addition bases of the longer S-ODNs offer more potential for non-specific contacts in the yield stronger intramolecular secondary structure, thereby reducing the likelihood of binding the telomerase target. It is known that the phosphorothioate oligonucleotides blocked the proliferation HIV-1 in infected cells in a nonsequence specific manner [43], probably the inhibition of reverse transcriptase [44,45] and/or the viral entry process [46,47]. Our previous study of the anti-HIV activities of antisense oligonucleotides indicated that a phosphorothioate oligonucleotide targeted to the HIV-1 gag gene was inhibitory, and the sense and the random sequence oligomers were also able to protect against HIV-1 induced CPE, but their anti-HIV-1 activities were weaker than that of the antisense phosphorothioate oligonucleotide (S-ODN-gag-AUG) [48].…”

Section: Resultsmentioning

confidence: 99%

Specific inhibition of human telomerase activity by transfection reagent,FuGENE6‐antisense phosphorothioate oligonucleotide complex inHeLa cells

et al. 1999

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Human telomerase might be associated with malignant tumor development and could be a highly selective target for antitumor drug design. Antisense phosphodiester (ODNs) and phosphorothioate (S-ODNs) oligonucleotides were investigated for their abilities to inhibit telomerase activity in the HeLa cell line. The ODNs and S-ODNs were designed to be complementary to nucleotides within the RNA active site of telomerase. As a transfection reagent, FuGENE6 was used to enhance the cellular uptake of oligonucleotides in cell cultures. The results showed that S-ODN-3 (19-mer) encapsulated with FuGENE6 clearly inhibited the telomerase activity in HeLa cells, and the inhibitory efficiency increased with an increase in the S-ODN-3. However, free S-ODN-3 showed no inhibitory activity. On the other hand, ODN-3 encapsulated with FuGENE6 had no detectable inhibitory activity. The encapsulated S-ODNs exhibited higher inhibitory activities than the free S-ODNs, and showed sequence specific inhibition. Thus, the activities of the S-ODNs were effectively enhanced by using the transfection reagent. The transfection reagent, FuGENE6, may thus be a potentially useful delivery vehicle for oligonucleotide-based therapeutics and transgenes, and is appropriate for use in vitro and in vivo.

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Phosphorothioate analogs of oligodeoxynucleotides: inhibitors of replication and cytopathic effects of human immunodeficiency virus.

Cited by 477 publications

References 22 publications

IL-2 deprivation triggers apoptosis which is mediated by c-Jun N-terminal kinase 1 activation and prevented by Bcl-2

IL-2 deprivation triggers apoptosis which is mediated by c-Jun N-terminal kinase 1 activation and prevented by Bcl-2

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

Specific inhibition of human telomerase activity by transfection reagent,FuGENE6‐antisense phosphorothioate oligonucleotide complex inHeLa cells

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