When proteins change their structure and clump together, formation of amyloid fibrils and plaques may occur. Such 'misfolding' and 'protein aggregation' processes damage cells and cause diseases such as Alzheimer's and type 2 diabetes. A team of scientists from the Technical University of Munich (TUM) headed by Professor Aphrodite Kapurniotu have now developed molecules that suppress protein aggregation and could pave the way for new treatments to combat Alzheimer's, type 2 diabetes and other cell-degenerative diseases.
The scientists designed and studied 16 different peptide molecules in order to find out which of them are able to impede the 'clumping' of the proteins amyloid beta (Aß) and islet amyloid polypeptide (IAPP), which are associated with Alzheimer's and type 2 diabetes.
The molecules were designed on the basis of scientific work that shows that the Aß and IAPP proteins interact with each other, and that this 'cross-amyloid interaction' suppresses their clumping. The researchers selected short sequences of the IAPP protein that correspond to the key regions involved in the interaction with the Alzheimer's protein. These "hot segments" were then chemically linked to each other by using specific peptide segments as 'linkers' in order to mimic and optimize the IAPP cross-amyloid interaction surface.
Powerful inhibitors block pathologically relevant amyloid proteins in Alzheimer's and diabetes
The work performed by Professor Kapurniotu's Peptide Biochemistry team at the TUM School of Life Sciences Weihenstephan together with researchers led by Professor Bernd Reif, TUM Department of Chemistry, and Professor Gerhard Rammes at Department of Anesthesiology, TUM Klinikum Rechts der Isar, identified among the designed molecules a number of powerful inhibitors of protein clumping. Three of the new peptide molecules suppressed cytotoxic clumping of both the Alzheimer's Aß and the type 2 diabetes IAPP. Another four designed peptides displayed selective inhibition of self-association of Aß; whereas one showed selective inhibition of IAPP clumping.
The results reveal a novel class of peptide leads that block misfolding and clumping of pathologically relevant amyloid proteins in Alzheimer's disease and type 2 diabetes, which could, in principle, be suitable for the development of therapeutics. In addition, the developed inhibitor design concept might find application in designing molecules that suppress disease-related interactions of other proteins as well.
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