(544a) Peptoid-Based Klvff Peptide Mimics to Inhibit Amyloid Beta Aggregation

Alzheimer’s disease (AD) is a neurological disorder that slowly develops, leading to dementia, rising healthcare expenses, and eventually death. AD is characterized by the build-up of the amyloid beta (Aβ) protein. As the Aβ proteins begin to aggregate, plaques form in the spaces between nerve cells, resulting in cellular death. Currently, there is no cure for AD; however, research has found that the peptide KLVFF is a key binding sequence for Aβ folding. By utilizing the peptide KLVFF sequence, researchers have shown to inhibit and speed up aggregation, as well as change the morphological state of Aβ. Unfortunately, peptide KLVFF has a low bioavailability. To overcome this, we have designed peptoid-based mimics of KLVFF to interact with Aβ. Structurally similar to peptides, peptoid side chain groups are amended to the amide group rather than the α-carbon. As a result, peptoids are immune to proteases and their small size is unlikely to induce an immune response, making peptoids ideal candidates for drug design.

Peptoid mimics were designed to mimic peptide KLVFF so peptoids could effectively bind to Aβ. Helical length, charge, and secondary structure were then investigated to determine peptoid-Aβ activity. Preliminary work has shown Aβ aggregation can be inhibited by 82-98% in 5-fold molar excess (peptoid inhibitor to Aβ monomer). Furthermore, we believe we can alter current peptoid sequences to develop a novel sequence that can inhibit Aβ aggregation in a 1:1 ratio or less of peptoid inhibitor to Aβ monomer and disaggregate fibrils.