The Effect of Retro-inverse D-Amino Acid Aβ-peptides on Aβ- Fibril Formation

Peptides build from D-amino acids resist enzymatic degradation. The resulting extended time of biological activity makes them prime candidates for the development of pharmaceuticals. Of special interest are D-retro inverso (DRI)peptides where a reversed sequence of D-amino acids leads to molecules with almost the same structure, stability and bioactivity as the parent L-peptides but increased resistance to proteolytic degradation. Here, we study the effect of DRI-A{beta}40 and DRI-A{beta}42 peptides on fibril formation. Using molecular dynamics simulations, we compare the stability of typical amyloid fibril models with such where the L-peptides are replaced by DRI-A{beta}40 and DRI-A{beta}42 peptides. We then explore the likelihood for cross fibrilization of A{beta} L-and DRI-peptides by investigating how presence of DRI peptides alters elongation and stability of L-A{beta}-fibrils. Our data suggest that full-length DRI-peptides may enhance the fibril formation and decrease the ratio of soluble toxic A{beta} oligomers, pointing out a potential for D-amino-acid-based drug design targeting Alzheimers disease.