9-Aminoellipticine-derivatized alpha- and beta-oligodeoxyribonucleotides targeted to the cap of beta-globin mRNA: hybridization to natural and engineered mRNA, inhibition of translation, and improved effect of tandem chains.

Porumb, H; Bertrand, J R; Paoletti, J; Vasseur, J J; Rayner, B; Imbach, J L; Malvy, C

Porumb, H; Bertrand, J R; Paoletti, J; Vasseur, J J; Rayner, B; Imbach, J L; Malvy, C.

Afiliación

Porumb H; Laboratoire de Biochimie-Enzymologie et de Physicochimie Macromoléculaire, CNRS URA 147, Institut Gustave Roussy, Villejuif, France.

Antisense Res Dev ; 2(4): 279-92, 1992.

Article en En | MEDLINE | ID: mdl-1292777

RESUMEN

We studied the duplex stability and the antimessenger activity of 9-aminoellipticine-5'-functionalized alpha- and beta-anomeric DNA sequences complementary to the first 14 nucleotides of the rabbit beta-globin mRNA. The duplex formed by the beta-conjugate with the natural mRNA target possessed a marginally better stability to that of the duplex formed by the unfunctionalized compound, as measured by the thermal elution. The alpha-conjugate did not anneal to native mRNA, possibly due to the interference of the 9-aminoellipticine with the cap structure and, unlike the beta-adduct, was practically inactive as inhibitor of translation in a cell-free system. However, it did hybridize to an RNA construction containing the beta-globin mRNA plus an additional 50 bases in 5'. Surprisingly, translation from this construction was inhibited by the alpha-species in spite of the nonvicinity of the target to the cap. Both alpha and beta conjugates hybridized to a DNA 14-mer of the same sequence as that targeted onto the mRNA. Thermal denaturation and fluorescence spectroscopy showed that the drug brought no considerable stabilization to the duplex, the linker presumably being unfavorable to intercalation. An increased stability of the complex and a higher inhibitory effect on cell-free beta-globin translation were obtained with two contiguous beta-oligomers of which one was functionalized.

Asunto(s)

Elipticinas/metabolismo; Globinas/genética; Oligonucleótidos Antisentido/metabolismo; Caperuzas de ARN/metabolismo; ARN Mensajero/metabolismo; Animales; Secuencia de Bases; Sistema Libre de Células; Sustancias Intercalantes/metabolismo; Datos de Secuencia Molecular; Desnaturalización de Ácido Nucleico; Ácidos Nucleicos Heterodúplex; Hibridación de Ácido Nucleico; Oligonucleótidos Antisentido/química; Oligonucleótidos Antisentido/genética; Plásmidos; Biosíntesis de Proteínas; Caperuzas de ARN/química; Caperuzas de ARN/genética; ARN Mensajero/química; ARN Mensajero/genética; Conejos; Espectrofotometría Ultravioleta; Temperatura

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Globinas / Caperuzas de ARN / ARN Mensajero / Oligonucleótidos Antisentido / Elipticinas Límite: Animals Idioma: En Revista: Antisense Res Dev Asunto de la revista: BIOLOGIA MOLECULAR Año: 1992 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos

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