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Molecular evolution of macrocyclic rescuers of disease-associated protein misfolding

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If you have a question about this talk, please contact Priyanka Joshi.

Protein misfolding is a common molecular feature for many human diseases, such as Alzheimer’s disease (AD), Parkinson’s disease, type II diabetes and others. We have developed an integrated and generalizable bacterial platform for facile discovery of macrocyclic rescuers of disease-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 misfolding using a genetic assay based on fluorescence-activated cell sorting. We will demonstrate the effectiveness of this approach through the identification of drug-like, head-to-tail cyclic peptides that modulate the aggregation of the amyloid β peptide (Aβ) of AD. Through a series of biochemical, biophysical and biological assays using isolated Αβ, primary mammalian neurons and various established AD models in the nematode Caenorhabditis elegans, the selected macrocycles have been found to inhibit the formation of neurotoxic Αβ aggregates. Further, to showcase the generality of our approach, we will describe the application of the same platform for the identification of misfolding rescuers of mutant Cu/Zn superoxide dismutase 1 (SOD1), a protein associated with inherited forms of amyotrophic lateral sclerosis. Overall, our approach represents a straightforward strategy for the discovery of molecules that rescue the misfolding of polypeptides known to be associated with disease effectively.

This talk is part of the Biophysical Seminars series.

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