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Biography

Georgios Skretas was graduated from the School of Chemical Engineering of the National Technical University of Athens, Greece in 1998 and received his PhD in Chemical Engineering from Princeton University, USA in 2006. He has then joined the University of Texas at Austin, USA to carry out Postdoctoral research training under the guidance of Professor George Georgiou. Since 2009, he has been the Principal Investigator of the Laboratory of Enzyme & Synthetic Biotechnology at the Institute of Biology, Medicinal Chemistry & Biotechnology of the National Hellenic Research Foundation, Greece, where he currently holds the rank of Research Assistant Professor.

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.

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