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Sequence Specific Recognition of the DNA Minor Groove by Im/Hp/Py Polyamides

The long range goal is a general chemical solution to unique recognition of any predetermined sequence in the human genome. Pairing rules have been developed to control rationally the DNA sequence specificity of minor-groove binding polyamides containing three aromatic ring amino acids, hydroxypyrrole (Hp), imidazole (Im), and pyrrole (Py). An Im/Py pair recognizes a G-C base pair, whereas a Py/Im combination targets a C-G base pair. An Hp/Py pair distinguishes T-A from A-T base pairs. Using a simple molecular shape and a three-letter amino-acid code, eight-ring pyrrole-imidazole polyamides achieve affinities and specificities comparable to DNA-binding proteins and, in addition, have the potential to be general for any desired DNA sequence. This non-biological approach to DNA recognition could provide an underpinning for the design of cell-permeable molecules for the control of gene-specific regulation in vivo.

An introduction to small molecule:DNA recognition may be found in a recent review: Peter B. Dervan, Bioorg. Med. Chem. 2001, 9:2215-2235.