Book Description

"Small molecules that can bind selectively to any predetermined DNA sequence in the human genome could potentially be powerful tools for molecular biology and human medicine. Polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) are small molecules that bind DNA according to a set of "pairing rules" with affinities and specificities similar to many naturally occurring DNA binding proteins. The study of DNA binding polyamides is further expanded by the development of new monomer pairings and new synthetic methods which allow access to polyamides with varying truncated tails. A new pairing of N-methylpyrazole with N-methylpyrrole increased specificity substantially without loss in affinity. This result indicates that other ring positions, besides the 3-position, can also greatly impact DNA recognition properties. Polyamides having truncated tails are shown to bind DNA with greater generality at the tail positions while maintaining high affinity, and may allow the targeting of a larger number of biologically relevant DNA sequences. Small molecules that bind DNA may offer a general approach to the chemical down- or up-regulation of gene expression by the inhibition or recruitment of transcription factors, respectively. Polyamide-peptide conjugates were synthesized and evaluated for their ability to activate transcription. A greater than 30-fold enhancement over basal levels was observed and activation could be correlated to DNA occupancy levels. Cys2His2 zinc finger proteins are the most common DNA binding motif in higher eukaryotes. We have elucidated an allosteric mechanism for the inhibition of zinc finger proteins, binding purely in the major groove, by Py/Im polyamides. The inhibition of this large class of proteins greatly enlarges the applicability of these minor groove ligands for gene regulation."