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All-d-Enantiomeric Peptide D3 Designed for Alzheimer's Disease Treatment Dynamically Interacts with Membrane-Bound Amyloid-β Precursors
Alzheimer’s disease (AD) is a severe neurodegenerative pathology with
no effective treatment known. Toxic amyloid-β peptide (Aβ) oligomers play a crucial
role in AD pathogenesis. All-D-Enantiomeric peptide D3 and its derivatives were
developed to disassemble and destroy cytotoxic Aβ aggregates. One of the D3-like
compounds is approaching phase II clinical trials; however, high-resolution details of its
disease-preventing or pharmacological actions are not completely clear. We
demonstrate that peptide D3 stabilizing Aβ monomer dynamically interacts with the
extracellular juxtamembrane region of a membrane-bound fragment of an amyloid
precursor protein containing the Aβ sequence. MD simulations based on NMR
measurement results suggest that D3 targets the amyloidogenic region, not
compromising its α-helicity and preventing intermolecular hydrogen bonding, thus
creating prerequisites for inhibition of early steps of Aβ conversion into β-
conformation and its toxic oligomerization. An enhanced understanding of the D3
action molecular mechanism facilitates development of effective AD treatment and prevention strategies.