A 2D Fragment-Assisted Protein Mimetic Approach to Rescue α-Synuclein Aggregation Mediated Early and Post-Disease Parkinsons Phenotypes

Abstract

We have developed a Oligopyridylamide (OP) based 2-Dimensional Fragment-Assisted Structure-based Technique (2D-FAST) to identify potent antagonists of -Synuclein (S) aggregation, a process central to Parkinsons disease (PD). The 2D-FAST utilizes a fragment-based screening of large chemical space in OPs, which led to the identification of NS132 as an antagonist of the multiple facets of S aggregation. We also identified a better cell permeability analog (NS163) without sacrificing activity. OPs rescue S aggregation mediated PD phenotypes in muscle cells and dopaminergic (DA) neurons in C. elegans models. OPs prevent the progression of PD phenotypes in a novel post-disease onset PD model. This is one of the first examples of a synthetic mimetic-based 2D-FAST to identify antagonists of toxic S self-assembly. We envision that 2D-FAST will have tremendous potential as it is expandable for other oligoamide scaffolds and for a much larger chemical space to identify lead therapeutics for various diseases.