Parkinson’s disease (PD) is a progressive neurodegenerative disorder for which there is no successful prevention or intervention. The pathological hallmark for PD involves the self-assembly of functional Alpha-Synuclein (αS) into non-functional amyloid structures. One of the potential therapeutic interventions against PD is the effective inhibition of αS aggregation. However, the bottleneck towards achieving this goal is the identification of αS domains/sequences that are essential for aggregation. Using a protein mimetic approach, we have identified αS sequences-based targets that are essential for aggregation and will have significant therapeutic implications. An extensive array of in vitro, ex vivo, and in vivo assays is utilized to validate αS sequences and their structural characteristics that are essential for aggregation and propagation of PD phenotypes. The study aids in developing significant mechanistic and therapeutic insights into various facets of αS aggregation, which will pave the way for effective treatments for PD.

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We have developed a Oligopyridylamide (OP) based 2-Dimensional Fragment-Assisted Structure-based Technique (2D-FAST) to identify potent antagonists of α-Synuclein (αS) aggregation, a process central to Parkinson’s 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 αS aggregation. We also identified a better cell permeability analog (NS163) without sacrificing activity. OPs rescue αS 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 αS 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.

Abberent protein−protein interactions (aPPIs) are associated with an array of pathological conditions, which make them important therapeutic targets. The aPPIs are mediated via specific chemical interactions that spread over a large and hydrophobic surface. Therefore, ligands that can complement the surface topography and chemical fingerprints could manipulate aPPIs. Oligopyridylamides (OPs) are synthetic protein mimetics that have been shown to manipulate aPPIs. However, the previous OP library used to disrupt these aPPIs was moderate in number (∼30 OPs) with very limited chemical diversity. The onus is on the laborious and time-consuming synthetic pathways with multiple chromatography steps. We have developed a novel chromatography-free technique to synthesize a highly diverse chemical library of OPs using a "common-precursor" approach. We significantly expanded the chemical diversity of OPs using a chromatography-free high-yielding method. To validate our novel approach, we have synthesized an OP with identical chemical diversity to a pre-existing OP-based potent inhibitor of Aβ aggregation, a process central to Alzheimer's disease (AD). The newly synthesized OP ligand (RD242) was very potent in inhibiting Aβ aggregation and rescuing AD phenotypes in an in vivo model. Moreover, RD242 was very effective in rescuing AD phenotypes in a post-disease onset AD model. We envision that our "common-precursor" synthetic approach will have tremendous potential as it is expandable for other oligoamide scaffolds to enhance affinity for disease-relevant targets.

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