The Purely Thermodynamic Anti-prionic Mode of Action for the Treatment of Neurodegenerative Diseases

Abstract

Neurodegenerative protein-misfolding diseases, like Alzheimer’s (AD) and Parkinson’s disease (PD), are driven by prion-like self-replicating and propagating protein assemblies of amyloid β (Aβ), α-synuclein, and many more. The conformation these proteins have in the aggregated state is thermodynamically more stable than their physiological monomer conformation, which is often intrinsically disordered. Therefore, we have developed all-D-enantiomeric peptide ligands that bind the monomeric protein of interest with high affinity, thereby stabilizing the physiological intrinsically disordered monomer structure. These ligands are eliminating already existing aggregates by disassembling them into monomers. This purely thermodynamic driven mode of action (MoA) is truly “anti-prionic”, because it is eliminating already existing oligomers and fibrils, thus disrupting prion-like replication and propagation of toxic protein aggregates. The MoA is realized by all-D-enantiomeric peptides that are specific for the target protein.