Targeting the transcriptional machinery with peptidomimetics

ORGN 674

Jean-Paul Desaulniers, jdesauln@umich.edu and Anna K. Mapp, amapp@umich.edu. Department of Chemistry, University of Michigan, 930 North University Ave, Ann Arbor, MI 48109
ESX is an epithelial transcription factor that modulates the expression of Her2, a growth-promoting transmembrane receptor protein. Upregulation of Her2 is often a hallmark in breast cancer and this overexpression is accomplished by recruiting the transcriptional coactivator, Sur2, to the promoter. The activation domain of ESX makes specific protein-protein contacts with Sur2 to initiate gene expression. The minimal activation domain of ESX responsible for Sur2 binding consists of an eight amino acid minimal sequence, SWIIELLE. The goal of this project is to better understand the binding interaction that exists between ESX and Sur2 in aims to design molecules that disrupt this interface. We have synthesized peptidomimetics based on the activation domain of ESX, and, using fluorescence polarization, we show that certain peptidomimetics bind Sur2. The results of peptides, peptidomimetics and other small molecule scaffolds will be described.