The purely thermodynamic anti-prionic mode of action for the treatment of neurodegenerative diseases - realized by target protein specific all-D-peptides.

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 Aβ, α-synuclein, and many more. Therefore, we have developed the so-called anti-prionic mode of action (MoA). It is realized by all-D-enantiomeric peptide ligands that bind the monomeric protein of interest with high affinity, thereby stabilizing the physiological intrinsically disordered monomer structure. We call this purely thermodynamic driven mode of action “anti-prionic”, because it is eliminating already existing prion-like aggregates by disassembling them into non-toxic and functional monomers. I will summarize the current, and yet unpublished, progress in realizing the anti-prionic MoA for the target proteins α-synuclein and Aβ. Briefly, the most promising all-D-enantiomeric ligand for α-synuclein, SVD-1a, disassembles preformed α-synuclein fibrils (PFF) as shown by AFM, DLS and SEC analysis. SPR and NMR demonstrate picomolar affinity of SVD-1a to α-synuclein monomers, while keeping them in their physiological intrinsically disordered conformation. The all-D-enantiomeric ligand for Aβ, RD2, disassembles Aβ oligomers obtained from brain tissue of former AD patients. A clinical phase Ib, double-bind, placebo-controlled study with 20 ATN positive patients treated once daily orally with RD2 or placebo for 4 weeks with an additional 4 weeks follow up period demonstrates good safety and tolerability, and yields interesting results on efficacy. This is valuable information for the scheduled phase II study. I will also acknowledge the many contributors of both developments that are too many to be included here in the abstract. Conclusion: The unique anti-prionic mode of action for the treatment of AD, PD and other protein misfolding diseases is promising.