All-D-peptides realize the purely thermodynamic anti-prionic mode of action for protein-misfolding diseases
Dieter Willbold
Director, Forschungszentrum Jülich
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. The conformation that these proteins have in their 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 by the free binding energy. These ligands are eliminating already existing aggregates by disassembling them into monomers. This purely thermodynamic driven mode of action is truly “anti-prionic”, because it is eliminating already existing oligomers and fibrils, thus disrupting prion-like replication and propagation of toxic protein aggregates.
I will summarize the current progress in realizing the anti-prionic MoA for the target proteins α-synuclein and Aβ.
Briefly, the all-D-enantiomeric ligand for α-synuclein, SVD-1, was discovered by mirror image phage display against the synthetic full-length α-synuclein monomers. A slightly optimized version, SVD-1a, disassembled preformed α-synuclein fibrils (PFF) as shown by AFM and DLS. SPR and NMR demonstrated picomolar affinity of SVD-1a to α-synuclein monomers, while keeping α-synuclein monomers in their physiological IDP conformation. This is essential for their roles in cellular function and signaling.
The all-D-enantiomeric ligand for Aβ, RD2, demonstrated ex vivo target engagement and disassembled Aβ oligomers obtained from brain tissue of former AD patients. The observed kinetic of this oligomer disassembly reaction resembles that of chaperone, indicating that RD2 acts catalytically. A clinical phase Ib, double-bind, placebo-controlled study with mild cognitively impaired (MCI) due to AD and mild AD patients treated once daily orally with RD2 or placebo for 4 weeks with an additional 4 weeks follow up period has been finished. I will present the results of this study, especially on good safety and tolerability, which are valuable information for the scheduled phase II study.
Conclusion: The promsing and unique anti-prionic mode of action for the treatment of AD, PD and other protein misfolding diseases is realized by all-D-peptides.
Dieter Willbold studied biochemistry in Tübingen (Germany), Bayreuth (Germany) and Boulder (Colorado, USA). He completed his PhD in 1994 at the University of Bayreuth. After some more years in Bayreuth and a couple of research visits, e.g. at the Sackler School of Medicine of the Tel-Aviv University, he was leading his junior research group at the Institute for Molecular Biotechnology in Jena, Germany. In 2001 Willbold became an associate Professor at the Heinrich Heine University in Düsseldorf. Since 2004, he is Full Professor at the Institute of Physical Biology in Düsseldorf and Director of the Institute of Complex Systems at the Forschungszentrum Jülich. His main interests are protein interactions with physiological and artificial ligands, high resolution structural biology, neurodegeneration, neuropathic pain and autophagy. Since quite some years, Willbold is very much engaged in drug development based on all-D-peptides for Alzheimer’s and other neurodegenerative diseases, and has co-founded the companies Priavoid and attyloid in 2017 and 2018, respectively.