Georgios Skretas
National Hellenic Research Foundation, Greece
Title: Engineering bacteria for the discovery of potential therapeutic compounds against protein misfolding diseases
Biography
Biography: Georgios Skretas
Abstract
It has now been widely recognized that many incurable diseases with enormous socioeconomic impact such as Alzheimer’s disease, Parkinson’s disease, type-2 diabetes etc., are initiated by a common mechanism; the misfolding of specific proteins. Here, we describe the use of engineered bacterial cells as a platform for the discovery of potential therapeutics against such protein misfolding diseases (PMDs). The topic of the described research is the application of molecular evolution approaches for the discovery of compounds that rescue the misfolding of PMD associated proteins. To achieve this, Escherichia coli cells are first engineered to biosynthesize large libraries of test compounds with high structural diversity. Then, the same cells are modified further so that they allow the identification of the rare molecules that correct the folding of particular misfolding-prone and PMD associated proteins (MisPs) with the use of a genetic screen. Lead compounds identified by this initial screen, are then subjected to more detailed evaluation by biochemical and biophysical methods of protein analysis and their ability to inhibit MisP induced pathogenicity is tested using appropriate human cell assays or in vivo models of the disease of interest. The molecules capable of rescuing the misfolding of the target MisP and of antagonizing its associated pathogenicity become drug candidates against the specific disease. We will describe our efforts to identify such “pharmacological chaperones” against the misfolding of the amyloid β (Aβ) peptide and of certain carcinogenic misfolded variants of human p53, with the aim of developing potentially therapeutic compounds against Alzheimer’s disease and cancer, respectively.