The design of small molecules that target specific DNA sequences in the double DNA helix can provide a new tool for control of gene expression and a rational basis for drug development. Hairpin polyamides containing N-methylimadazole and N-methylpyrrole amino acids are synthetic ligands that bind to predetermined DNA sequences with affinities and specificities comparable to naturally occurring DNA binding proteins. The goal of this project is to investigate the use of these compounds as inhibitors of viral gene expression, specifically CMV gene expression. We propose to develop synthetic polyamides that will specifically interrupt the binding of transcription factors to regulatory sequences within the CMV genome. In the first aim we will design and generate polyamides capable of recognizing specific sequences adjacent to binding sites for key cellular transcription factors used by two crucial CMV promoters, the major immediate early and DNA polymerase promoters. In the second aim we will characterize the activity of these compounds on viral gene expression and virus replication in-vitro.
The third aim will extend these studies to an animal model, MCMV infection in mice. In the fourth and final aim, we will determine if these compounds can inhibit reactivation from latency. The results of this study will represent a step towards determining whether these small molecule transcriptional antagonists could be considered as agents for treatment of human disease.
