Rapid Selection of Cyclic Peptides that Reduce α-Synuclein Toxicity in Yeast and Animal Models

Phage display has demonstrated the utility of cyclic peptides as general protein ligands, but cannot access proteins inside eukaryotic cells. Expanding a novel chemical genetics tool, we describe the first expressed library of head-to-tail cyclic peptides in yeast (Saccharomyces cerevisiae). We applied the library to selections in a yeast model of α-synuclein toxicity that recapitulates much of the cellular pathology of Parkinson’s disease. From a pool of five million transformants, we isolated two related cyclic peptide constructs which specifically reduce the toxicity of human α-synuclein. These expressed cyclic peptide constructs also prevent dopaminergic neuron loss in an established Caenorhabditis elegans Parkinson’s model. This work highlights the speed and efficiency of using libraries of expressed cyclic peptides for forward chemical genetics in cellular models of human disease.