Dna-binding pyrrole and imidazole polyamide derivatives

C - Chemistry – Metallurgy – 07 – K

Patent

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Details

C07K 14/00 (2006.01) A61K 31/4178 (2006.01) A61P 43/00 (2006.01) C07D 403/14 (2006.01) C07K 7/00 (2006.01) C07K 7/04 (2006.01)

Patent

CA 2286232

Novel small molecule polyamides of Formula (I) that specifically bind with subnanomolar affinity to any predetermined sequence in the human genome with potential use in molecular biology and human medicine are described. Further, the designed compounds which target the minor groove of B-form double helical DNA offer a general approach for the control of gene-expression. Simple rules are disclosed which provide for rational control of the DNA-binding sequence specificity of synthetic polyamides containing N-methylpyrrole and N- methylimidazole amino acids. A series of molecular templates for polyamide design are disclosed which provide for small molecules which recognize predetermined DNA sequences with affinities and specificities comparable to sequence specific DNA-binding proteins such as transcription factors.

L'invention concerne de nouvelles petites molécules de polyamides de formule (I) qui lient spécifiquement, avec une affinité sub-nanomolaire, n'importe quelle séquence prédéterminée du génome humain, et qui pourraient être utilisées en biologie moléculaire et en médecine humaine. Ces composés conçus de manière rationnelle, qui ciblent le sillon mineur d'un ADN en double hélice de forme B, offrent une approche générale du contrôle de l'expression génétique. L'invention propose des règles simples qui permettent de contrôler rationnellement la spécificité de la séquence de liaison de l'ADN pour les polyamides synthétiques contenant des acides aminés N-méthylpyrrole et N-méthylimidazole. L'invention concerne également une série de matrices moléculaires destinées à la conception rationnelle des polyamides et permettant de créer des petites molécules qui reconnaissent des séquences d'ADN prédéterminées, et dont l'affinité et la spécificité sont comparables à celles des protéines de liaison de l'ADN telles que les facteurs transcriptionnels.

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