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

Abstract

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.

“Common-Precursor” Protein Mimetic Approach to Rescue Aβ Aggregation-Mediated Alzheimer’s Phenotypes

“…The excess primary amine and base were dried via lyophilization, which left the final product (pyridyl with amine side chains) in pure form. The appending of the primary amines as side chains on the OPs has also been reported recently by us . Here, we synthesized an OP library to demonstrate the feasibility of our novel approach (Figure ).…”

“…OPs have shown desirable pharmaceutical properties in mouse models for other amyloid targets due to their non-proteogenic side chains and an aromatic backbone scaffold . Additionally, the OPs can be synthetically modified to tune the pharmacological properties without sacrificing the antagonist activity . In the near future, the potent OP ligand identified here will be tested for its ability to cross the blood–brain barrier, which is a requirement for drugs to treat neurological disorders.…”

“…All strains were maintained using previous protocols. 50,51,57,58 NGM agar plates, M9 buffer (3 g of KH 2 PO 4 , 6 g of Na 2 HPO 4 , 5 g of NaCl, 1 mL of 1 M MgSO 4 , Milli-Q H 2 O to 1 L), and OP50 solution at 0.5 optical density (OD 600nm ) were prepared using previous protocols. 50 Motility Rate Assay for GMC101 Strain Treated with Ligands.…”

A “Common-Precursor” Protein Mimetic Approach to Rescue Aβ Aggregation-mediated Alzheimer’s Phenotypes

“…Additionally, the OPs can be synthetically modified to tune the pharmacological properties without sacrificing the antagonist activity. 51 In the near future, the potent OP ligand identified here will be tested for its ability to cross the blood-brain barrier, which is a requirement for drugs to treat neurological disorders. These studies are underway and will be presented in the near future.…”

“…All strains were maintained using previous protocols. 50,51,57,58 NGM agar plates, M9 buffer (3 g KH2PO4, 6 g Na2HPO4, 5 g NaCl, 1 mL 1 M MgSO4, milli-Q H2O to 1 L), and OP50 solution at 0.5 Optical Density (OD600nm) were prepared using previous protocols 50 .…”