All<i>-</i><scp>d</scp><i>-</i>Enantiomeric Peptide D3 Designed for Alzheimer’s Disease Treatment Dynamically Interacts with Membrane-Bound Amyloid-β Precursors
Eduard V. Bocharov, Lothar Gremer, Anatoly S. Urban, I.S. Okhrimenko, Pavel E. Volynsky, Kirill D. Nadezhdin, Olga V. Bocharova, Daniil A. Kornilov, Yuliya A. Zagryadskaya, A. V. Kamynina, Pavel Kuzmichev, Janine Kutzsche, Najoua Bolakhrif, Andreas Müller‐Schiffmann, Norbert A. Dencher, Alexander S. Arseniev, Roman G. Efremov, Valentin Gordeliy, Dieter Willbold
Abstract
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.