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.