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 seven-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 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.

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