Effect of Antisense Oligonucleotides Linked to Alkylating Agents on In Vitro Translation of Rabbit β-Globin and<i>Typuaosomu brucei</i>mRNAs

Boiziau, Claudine; Boutorine, Alexandre S.; Loreau, Nadine; Verspieren, P.; Thuong, Nguyen T.; Toulmé, Jean Jacques

doi:10.1080/07328319108046451

Cited by 9 publications

(3 citation statements)

References 11 publications

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“…The long lifetime of these compounds due to their nuclease resistance could make them very interesting compounds with intact cells. Moreover, linking these oligomers to reactive groups such as psoralen or alkylating reagents could allow targeting the coding region as demonstrated recently (37,38). This results in effective antisense compounds that could act even in the absence of any RNase-H activity.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of translation initiation by antisense oligonucleotides via an RNase-H independent mechanism

Boiziau¹,

Kurfürst

Cazenave³

et al. 1991

Nucl Acids Res

139

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We have used alpha-oligomers as antisense oligonucleotides complementary to three different sequences of the rabbit beta-globin mRNA: a region adjacent to the cap site, a region spanning the AUG initiation codon or a sequence in the coding region. These alpha-oligonucleotides were synthesized either with a free 5' OH group or linked to an acridine derivative. The effect of these oligonucleotides on mRNA translation was investigated in cell-free extracts and in Xenopus oocytes. In rabbit reticulocyte lysate and in wheat germ extracts oligomers targeted to the cap site and the initiation codon reduced beta-globin synthesis in a dose-dependent manner, whereas the target mRNA remained intact. The anti-cap alpha-oligomer was even more efficient that its beta-counterpart in rabbit reticulocyte lysate. In contrast, only the alpha-oligomer, linked to the acridine derivative, complementary to the cap region displayed significant antisense properties in Xenopus oocytes. Therefore initiation of translation can be arrested by oligonucleotide/RNA hybrids which are not substrates for RNase-H.

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Section: Discussionmentioning

confidence: 98%

Inhibition of translation initiation by antisense oligonucleotides via an RNase-H independent mechanism

Boiziau¹,

Kurfürst

Cazenave³

et al. 1991

Nucl Acids Res

139

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“…Antisense effects of phosphodiester and phosphorothioate ODNs targeted to sequences in the coding region of a mRNA are RNase H dependent (7,26,(32)(33). ODN analogs that do not activate RNase H (as mentioned above) are capable of blocking translation at targets in the coding region only when conjugated to crosslinkers, such as psoralen (34)(35)(36), or to alkylating reagents (37)(38). In agreement with previous findings (8,(22)(23), we here show that a PNA forming a (PNA) 2 /RNA triplex in the coding region of CAT mRNA causes arrest of the elongating ribosome, giving rise to a truncated protein product.…”

Section: Discussionmentioning

confidence: 99%

Antisense Properties of Duplex- and Triplex-Forming PNAs

Knudsen¹,

Nielsen²

1996

Nucleic Acids Research

261

164

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The potential of peptide nucleic acids (PNAs) as specific inhibitors of translation has been studied. PNAs with a mixed purine/pyrimidine sequence form duplexes, while homopyrimidine PNAs form (PNA)2/RNA triplexes with complementary sequences on RNA. We show here that neither of these PNA/RNA structures are substrates for RNase H. Translation experiments in cell-free extracts showed that a 15mer duplex-forming PNA blocked translation in a dose-dependent manner when the target was 5'-proximal to the AUG start codon on the RNA, whereas similar 10-, 15- or 20mer PNAs had no effect when targeted towards sequences in the coding region. Triplex-forming 10mer PNAs were efficient and specific antisense agents with a target overlapping the AUG start codon and caused arrest of ribosome elongation with a target positioned in the coding region of the mRNA. Furthermore, translation could be blocked with a 6mer bisPNA or with a clamp PNA, forming partly a triplex, partly a duplex, with its target sequence in the coding region of the mRNA.

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“…Nonionic oligonucleotide analogs and oligonucleotides built of o~-anomeric nucleotides do not promote RNA's cleavage by ribonuclease H; when targeted to the coding region of mRNAs, they do not affect the functions of the messengers. Supplied with reactive groups, these analogs are converted into powerful translation inhibitors (Boiziau et al, 1991;Kean et al, 1988).…”

Section: Arrest Of Translation and Transcriptionmentioning

confidence: 99%

Reactive oligonucleotide derivatives as gene-targeted biologically active compounds and affinity probes

Knorre

Vlassov

1991

Genetica

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Development of efficient methods for synthesis of oligonucleotides and oligonucleotide analogs has opened up the possibility of designing a broad spectrum of affinity reagents for specific modification of nucleic acids and proteins. These affinity reagents are used for investigation of the topology of ribosomes and nucleic acid polymerases. Oligonucleotides and their analogs are already used for suppression of specific gene expression and for elucidation of the physiological role of their products. Oligonucleotide derivatives appear to offer considerable promise as potential gene-targeted drugs such as antivirals and specific inhibitors of oncogene expression.

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Effect of Antisense Oligonucleotides Linked to Alkylating Agents on In Vitro Translation of Rabbit β-Globin andTypuaosomu bruceimRNAs

Cited by 9 publications

References 11 publications

Inhibition of translation initiation by antisense oligonucleotides via an RNase-H independent mechanism

Inhibition of translation initiation by antisense oligonucleotides via an RNase-H independent mechanism

Antisense Properties of Duplex- and Triplex-Forming PNAs

Reactive oligonucleotide derivatives as gene-targeted biologically active compounds and affinity probes

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