Synthetic Peptides as basis for multifunctional drugs in ...

In Alzheimer's, Parkinson's, and type 2 diabetes, harmful protein aggregates and deposits, known as amyloid plaques, develop. There is also much evidence that these three diseases are interconnected and mutually reinforcing. A research team led by the Technical University of Munich (TUM) has now shown that synthetic mini-proteins (macrocyclic peptides) developed by the researchers inhibit both amyloid formation in Parkinson's and harmful protein interactions between the three diseases in experimental models. They could serve as the basis for future drugs to treat these diseases.

Astrid Eckert / TUM

Aphrodite Kapurniotu in the laboratory with some of the researchers involved (from left to right: Beatrice Dalla Volta, Aphrodite Kapurniotu, Beatrice Marcon, and Simon Hornung)

To date, no medication can prevent the development of Alzheimer's, Parkinson's, or type 2 diabetes. Yet the urgency to take action is high because as life expectancy increases, so does the number of people who develop one of these diseases in the course of their lives. In addition, recent research has shown complex connections between the three diseases. For example, patients with type 2 diabetes have an increased risk of developing Parkinson's or Alzheimer's disease as well. Furthermore, interactions between the amyloid-forming proteins of the individual diseases can accelerate and intensify the damaging protein aggregation in the other diseases.

In experimental models, a team led by Aphrodite Kapurniotu, Professor of Peptide Biochemistry at TUM, has now succeeded in inhibiting the formation of protein aggregates in Parkinson's disease with the help of so-called macrocyclic peptides. Moreover, these peptides also suppress harmful interactions between the proteins of the three diseases. They mimic certain features in the structure of one of the proteins. This enables them to dock onto amyloid-forming proteins of the three diseases. Their interactions are blocked and amyloid formation is prevented.

Astrid Eckert / TUM

Prof. Aphrodite Kapurniotu

With this discovery, the researchers are building on earlier studies. In these, they used the peptides in experimental models to prevent the formation of amyloid protein aggregates, which occur in Alzheimer's disease and type 2 diabetes.

Patent applications have already been filed. "Further research is needed before suitable drugs can be launched. However, we think that our peptides are valuable candidates for the development of effective drugs for treating Parkinson's, Alzheimer's, diabetes, and their co-occurrence," says Aphrodite Kapurniotu.

Publications

Hornung, S., Vogl, D. P., Naltsas, D., et al.: A. Multi-Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self- and Cross-Seeded Amyloid Self-Assembly of α-Synuclein. (2025) Angew Chem Int, https://doi.org/10.1002/anie.202422834

Spanopoulou, A., Heidrich, L., Chen, H. R., et al.: A. Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements. (2018) Angew Chem Int,  https://doi.org/10.1002/anie.201802979

Further information and links

• Aphrodite Kapurniotu is a Professor of Peptide Biochemistry at the TUM School of Life Sciences.

• The team collaborated with the research groups of Prof. Hilal A. Lashuel (EPFL), Prof. Dr. Jürgen Bernhagen (LMU University Hospital Munich, LMU), Dr. Regina Feederle (Helmholtz Center Munich German Research Center for Environmental Health), PD Dr. Thomas Koeglsperger and Prof. Dr. Günter Höglinger (LMU University Hospital Munich, LMU) and Prof. Dr. Gerhard Rammes (TUM University Hospital).

• The research work was primarily funded by the German Research Foundation (DFG) as part of the SFB 1035 (spokesperson Prof. Dr. Johannes Buchner, TUM).