A new class of designed macrocyclic peptides that are highly potent inhibitors of amyloid formation are described in new research by scientists at the Technical University of Munich.

The work brings effective therapeutics to counteract the formation of amyloid plaques in Alzheimer’s disease and type 2 diabetes a small step closer.

Amyloid plaques, which are protein deposits, play a crucial role in the development of Alzheimer’s disease and type 2 diabetes. Several teams of scientists around the world are working on finding ways to prevent amyloid plaque formation in the human brain.

Macrocyclic Peptides

The research team of Aphrodite Kapurniotu, Professor for Peptide Biochemistry (TUM) has been working on an idea for some time now in collaboration with the teams of Professor Martin Zacharias (TUM), Professor Gerhard Rammes (TUM Rechts der Isar Hospital) and Professor Jürgen Bernhagen (Institute for Stroke and Dementia Research (ISD) at Ludwig Maximilian University (LMU)).

[caption id=“attachment_96876” align=“aligncenter” width=“680”]macrocyclic peptides Credit: Kapurniotu/ TUM[/caption]

The researchers have presented macrocyclic peptides (MCIPs) as potent inhibitors of amyloid formation.

“We have discovered an MCIP that is stable in human blood plasma and can also overcome the human blood-brain barrier in an in vitro cell culture model. So far we were only able to demonstrate these properties in the test tube—thus, further research is necessary. But these are two highly desirable properties for inhibitors of Alzheimer’s amyloid,"

explained Professor Kapurniotu.

Promising Alternative Therapeutic

TUM has already applied for a patent for the newly developed macrocyclic peptides.

“They could be a good alternative to the currently pursued antibody-based approaches as therapeutics against Alzheimer’s amyloid plaque formation because they are easy to produce, have promising properties and, due to their peptidic nature, they will be significantly cheaper than antibodies,"

said Professor Kapurniotu.

“Therefore, further investigations are now planned to verify whether the MCIPs are also effective in in vivo models. Furthermore, the MCIPs could also be suitable as templates for the development of small molecule peptidomimetics (molecules mimicking peptide chains), which might also find application as anti-amyloid drugs in Alzheimer’s and type 2 diabetes,"

she adds.

Macrocyclic peptides are one the most attractive classes of drug candidates; they often blend highly favourable properties like high activity and target selectivity, a large surface area, high binding affinity, improved stability in bio-fluids and cell permeability.

Spanopoulou, A., Heidrich, L., Chen, H., Frost, C., Hrle, D., Malideli, E., Hille, K., Grammatikopoulos, A., Bernhagen, J., Zacharias, M., Rammes, G. and Kapurniotu, A. Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements Angew. Chem. Int. Ed.  doi:10.1002/anie.201802979

Image: Odra Noel, Wellcome Images

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