Fig. 1: Mechanistic model of the anti-prionic mode of action realized by the all-d peptide described in the present work.

Anti-prionic all-d-peptides are designed to stabilize monomers in their intrinsically disordered conformation—symbolized by circles. This conformation is distinct from the yet unknown, but certainly highly defined beta-sheet-rich conformation building blocks in oligomers—symbolized by hexagons. A Qualitative and schematic free energy landscape for the anti-prionic mode of action. The black line represents the energy landscape in the absence of the anti-prionic all-d-peptide. Monomer building blocks in oligomers are more stable than monomers. This allows the formation of oligomers from monomers thermodynamically, although there is a kinetic barrier, which is called primary nucleation and is currently under intensive investigation. Stabilization of the monomer by the anti-prionic all-d-peptide is lowering the free energy of the monomer (light green line) when in complex with the all-d-peptide, by the free binding energy (blue arrow) of the complex. Because in the presence of the anti-prionic all-d-peptide, the monomer has a lower free energy as compared to the oligomer, oligomers are disassembled into monomers. B Mechanistic model for disassembly of already existing oligomers from top to bottom: Anti-prionic all-d-peptides—symbolized by circle segments—approach oligomers. Due to their affinity to α-syn monomers, each all-d-peptide will interact with one of the α-syn building blocks within the oligomer assembly and thereby pushes its conformation towards the intrinsically disordered monomer conformation. This is incompatible with the oligomer assembly and therefore destabilizing the oligomer assembly. Further destabilization by interaction of additional anti-prionic molecules with other monomer building blocks ultimately leads to the complete disassembly of the oligomer into monomers in their intrinsically disordered conformation. Both molecules remain disordered in this transient complex, which may therefore be called “fuzzy complex”³¹. We called this mode of action “anti-prionic”, because it is ultimately disrupting prion-like behaving aggregates¹².