Psysol 2 as a novel research tool for prolyl oligopeptidase

The enzyme Prolyl oligopeptidase cleaves short peptide substrates with a central proline residue. Growing evidence exists that indicates the enzyme has a large protein interaction network. Amongst others, alpha-synuclein, which becomes pathogenic in Parkinsons disease when protein aggregates occur during the progression of the disease, interacts with prolyl oligopeptidase. Other proteins in the network modulate autophagy and clearance of protein aggregates in neurons. Hence, the modulation of prolyl oligopeptidase and its protein network holds promise for a novel mechanism, which, in the future, may be interesting for a therapeutic purpose toward alpha-synucleinopathies. We have identified a first-of-its-class modulator of prolyl oligopeptidase, the peptide psysol 2, from the tropical plant Psychotria solitudinum. Psysol 2 is a cyclic cystine-rich peptide (cyclotide), which are expressed in Viola, Squash, Pea and in many plants from the coffee family. Due to its stabilized structure that is based on the cyclic cystine knot motif, the molecule comprises many drug-like features. Psysol 2 will be used as starting point to study the modulation of prolyl oligopeptidase and its protein network. The peptide-protein interaction will be investigated with structural biology and the gained information will be used to chemically tailor psysol 2. The alpha-synuclein dimerization, the formation of aggregates as well as its toxic oligomers will be studied with the help of several in vitro models to elucidate the effects of the novel modulator of prolyl oligopeptidase. Overall, this research project will provide proof of concept for macrocyclic peptide scaffolds as modulators of prolyl oligopeptidase. If successful, we will provide evidence for a possible new therapeutic approach that uses aggregation modulators to ameliorate pathogenic processes in alpha-synucleinopathies, e.g. Parkinsons Disease. Abstract engl