Small molecule polyamides 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. These design rule are applied to provide a polyamide for specific targeting of a predetermined 7 base pair sequence from a conserved HIV gene promoter at subnanomolar concentration. The pyrrole-imidazole polyamides described herein represent the only class of designed small molecules to date that can bind any predetermined sequence of double helical DNA.

 
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