Completion of a programmable DNA-binding small molecule library

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 (Ka) range from K-a = 1 x 10(8) to 4 x 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. (c) 2007 Elsevier Ltd. All rights reserved.