Selective inhibition of internally initiated rna translation

Details Selective inhibition of internally initiated rna translation Selective inhibition of internally initiated rna translation

C - Chemistry, Metallurgy

07

H

C07H 21/02 (2006.01) A61K 31/70 (2006.01) A61K 31/7088 (2006.01) A61K 31/7105 (2006.01) A61K 48/00 (2006.01) A61P 31/12 (2006.01) C07H 21/00 (2006.01) C12N 15/10 (2006.01) C12N 15/11 (2006.01) C12Q 1/68 (2006.01) G01N 33/53 (2006.01) G01N 33/543 (2006.01) A61K 38/00 (2006.01)

Patent

CA 2201702

A method to inhibit translation of an mRNA, which is intitiated at an internal ribosome entry site of the mRNA and requires binding of a protein factor to that site, is disclosed. The method comprises a step of providing, in an in vitro, or in vivo system that is capable of translating the mRNA, an inhibitory effective amount of a molecule that selectively binds to the protein factor, thereby preventing that factor from binding to the mRNA. The inhibitor molecule is an RNA oligonucleotide consisting of less than 35 nucleotides or a structural mimic of such an RNA oligonucleotide. Nucleotide sequences of such inhibitor RNA oligonucleotides include portions of the following sequences: the 60 nucleotide sequence of a yeast inhibitor RNA or of the sequence complementary to that yeast inhibitor RNA; nucleotides 186-220 of poliovirus (stem-loop D); nucleotides 578-618 of poliovirus (stem-loop G); nucleotides 260-415 of poliovirus (stem-loop E); nucleotides 448-556 of poliovirus (stemp-loop F); and the sequence of the internal ribosome entry site of the immunoglobulin heavy chain binding protein (Bip).

L'invention concerne un procédé d'inhibition de la traduction d'un ARNm, laquelle est initiée au niveau d'un site d'entrée de ribosome interne de l'ARNm et nécessite la fixation d'un facteur protéique sur ce site. Le procédé comprend une étape consistant à fournir, dans un système in vitro ou in vivo capable de traduire l'ARNm, une quantité inhibitrice efficace d'une molécule se fixant sélectivement au facteur protéique, empêchant ainsi ce facteur de se fixer à l'ARNm. La molécule inhibitrice est un oligonucléotide d'ARNm constitué de moins de 35 nucléotides ou d'un imitateur structurel de cet oligonucléotide d'ARN. Des séquences nucléotidiques de ces oligonucléotides d'ARN inhibiteurs présentent des parties des séquences suivantes: la séquence de 60 nucléotides d'un ARN inhibiteur de levure ou la séquence complémentaire à cet ARN inhibiteur de levure; les nucléotides 186-220 de poliovirus (tige-boucle D); les nucléotides 578-618 de poliovirus (tige-boucle G); les nucléotides 260-415 de poliovirus (tige-boucle E); les nucléotides 448-556 de poliovirus (tige-boucle F); et la séquence du site d'entrée de ribosome interne de la protéine de liaison (Bip) des chaînes lourdes de l'immunoglobuline.

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