The effect of retro-inverse D-amino acid Aβ-peptides on Aβ-fibril formation

• Published in: The Journal of chemical physics Vol. 150; no. 9; p. 095101
• Main Authors: Xi, Wenhui, Hansmann, Ulrich H E
• Format: Journal Article
• Language: English
• Published: United States 07-03-2019
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Amino Acids - chemistry; Amino Acids - metabolism; Amyloid - antagonists & inhibitors; Amyloid - chemical synthesis; Amyloid - chemistry; Drug Design; Humans; Molecular Dynamics Simulation; Solubility; Stereoisomerism
• ISSN: 1089-7690
• DOI: 10.1063/1.5082194

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-Aβ
and DRI-Aβ
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-Aβ
and DRI-Aβ
peptides. We then explore the likelihood for cross fibrilization of Aβ L- and DRI-peptides by investigating how the presence of DRI peptides alters the elongation and stability of L-Aβ-fibrils. Our data suggest that full-length DRI-peptides may enhance the fibril formation and decrease the ratio of soluble toxic Aβ oligomers, pointing out potential for D-amino-acid-based drug design targeting Alzheimer's disease.