BEGIN:VCALENDAR VERSION:2.0 PRODID:-//Talks.cam//talks.cam.ac.uk// X-WR-CALNAME:Talks.cam BEGIN:VEVENT SUMMARY:Molecular evolution of macrocyclic rescuers of disease-associated protein misfolding - Dr. Georgios Skretas\, Research Assistant Professor\, Institute of Biology\, Medicinal Chemistry &\; Biotechnology\, Nationa l Hellenic Research Foundation\, Athens\, Greece DTSTART:20170531T093000Z DTEND:20170531T103000Z UID:TALK72813@talks.cam.ac.uk CONTACT:Priyanka Joshi DESCRIPTION:Protein misfolding is a common molecular feature for many huma n diseases\, such as Alzheimer’s disease (AD)\, Parkinson’s disease\, type II diabetes and others. We have developed an integrated and generaliz able bacterial platform for facile discovery of macrocyclic rescuers of di sease-associated protein misfolding. In this system\, large combinatorial libraries of macrocycles are biosynthesized in Escherichia coli cells and simultaneously screened for their ability to rescue pathogenic protein mis folding using a genetic assay based on fluorescence-activated cell sorting . We will demonstrate the effectiveness of this approach through the ident ification of drug-like\, head-to-tail cyclic peptides that modulate the ag gregation of the amyloid β peptide (Aβ) of AD. Through a series of bioch emical\, biophysical and biological assays using isolated Αβ\, primary m ammalian neurons and various established AD models in the nematode Caenorh abditis elegans\, the selected macrocycles have been found to inhibit the formation of neurotoxic Αβ aggregates. Further\, to showcase the general ity of our approach\, we will describe the application of the same platfor m for the identification of misfolding rescuers of mutant Cu/Zn superoxide dismutase 1 (SOD1)\, a protein associated with inherited forms of amyotro phic lateral sclerosis. Overall\, our approach represents a straightforwar d strategy for the discovery of molecules that rescue the misfolding of po lypeptides known to be associated with disease effectively. LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre END:VEVENT END:VCALENDAR