James K Bashkin
University of Missouri-St. Louis, USA
Title: Polyamides as multifaceted molecules for medicinal chemistry
Biography
Biography: James K Bashkin
Abstract
We describe polyamides active against human papillomavirus (HPV), vesicular stomatitis virus (VSV), and the ETS superfamily transcription factor PU.1. The MWs of active polyamides range from high to low, and cell uptake by an active mechanism was observed for human keratinocytes infected with HPV. In the case of VSV, X-ray crystallography revealed a polyamide bound to both the viral negative strand RNA genome and the nucleocapsid proteins, and biophysical studies showed changes to the melting temperature of the nucleocapsid-like particle (NLP) in the presence of the active compound, which protected cells from virally induced lysis. Polyamides were not to bind well to RNA. In the case of PU.1, a protein that binds the major groove of DNA, we designed inhibitors using minor groove-binding polyamides. However, one polyamide formed a ternary complex with PU.1 and DNA, causing weak but measurable stabilization of the PU.1-DNA complex. The ternary complex was observed by a variety of analytical techniques, as will be described. This strengthening of protein-DNA binding for a transcription factor by an unadorned polyamide is unexpected and novel, given that large molecular architectures have previously been required to achieve similar effects