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Current Medicinal Chemistry
ISSN (Print): 0929-8673
ISSN (Online): 1875-533X
VOLUME: 21
ISSUE: 12
DOI: 10.2174/0929867321666131129122247      Price:  $58









Amyloid Aggregation Inhibitory Mechanism of Arginine-rich D-peptides

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Author(s): O.O. Olubiyi, D. Frenzel, D. Bartnik, J.M. Gluck, O. Brener, L. Nagel-Steger, S.A. Funke, D. Willbold and B. Strodel
Pages 1448-1457 (10)
Abstract:
It is widely believed that Alzheimer's disease pathogenesis is driven by the production and deposition of the amyloid-β peptide (Aβ) in the brain. In this study, we employ a combination of in silico and in vitro approaches to investigate the inhibitory properties of selected arginine-rich D-enantiomeric peptides (D-peptides) against amyloid aggregation. The D-peptides include D3, a 12-residue peptide with anti-amyloid potencies demonstrated in vitro and in vivo, RD2, a scrambled sequence of D3, as well as truncated RD2 variants. Using a global optimization method together with binding free energy calculations followed by molecular dynamics simulations, we perform a detailed analysis of D-peptide binding to Aβ monomer and a fibrillar Aβ structure. Results obtained from both molecular simulations and surface plasmon resonance experiments reveal a strong binding of D3 and RD2 to Aβ, leading to a significant reduction in the amount of β structures in both monomer and fibril, which was also demonstrated in Thioflavin T assays. The binding of the D-peptides to Aβ is driven by electrostatic interactions, mostly involving the D-arginine residues and Glu11, Glu22 and Asp23 of Aβ. Furthermore, we show that the anti-amyloid activities of the D-peptides depend on the length and sequence of the Dpeptide, its ability to form multiple weak hydrophobic interactions with Aβ, as well as the Aβ oligomer size.
Keywords:
Amyloid beta, amyloid inhibition, D-peptides, in silico, surface plasmon resonance, ThT assay.
Affiliation:
Forschungszentrum Jülich, Institute of Complex Systems: Structural Biochemistry (ICS-6), 52425 Jülich, Germany.