Completion of a Programmable DNA-Binding Small Molecule Library

Abstract

Hairpin pyrrole-imidazole (Py-Im) polyamides are programmable oligomers that bind the DNA minor groove in a sequence-specific manner with affinities comparable to those of natural DNA-binding proteins. These cell-permeable small molecules have been shown to enter the nuclei of live cells and downregulate endogenous gene expression. We complete here a library of 27 hairpin Py-Im polyamides which bind 7-base-pair sequences of the general form 5'-WWGNNNW-3' (where W = A or T, N = W, G, or C). Their equilibrium association constants (K(a)) range from K(a) = 1×10(8) M(-1) to 4×10(10) M(-1) with good sequence specificity. A table of binding affinities and sequence contexts for this completed 27-member library has been assembled for the benefit of the chemical biology community interested in molecular control of transcription.

Figure 1

(Top) Model for the complex formed between hairpin polyamide 24 and its match DNA sequence. Circles with two dots represent the lone pairs of N(3) of purines and O(2) of pyrimidines. Circles containing an H represent the N(2) hydrogen of G. Hydrogen bonds are illustrated by dotted lines. (Bottom) Ball-and-stick binding model for the hairpin motif with the polyamide bound to its target DNA sequence. Imidazole and pyrrole are shown as filled and non-filled circles, respectively; β-alanine is shown as a diamond; the dimethylaminopropylamide tail is shown as a half-circle with a plus; and the chiral diaminobutyric acid turn residue is shown as a semicircle linked to a half-circle with a plus connecting the two subunits.