All-d-Enantiomeric Peptide D3 Designed for Alzheimer’s Disease Treatment Dynamically Interacts with Membrane-Bound Amyloid-β Precursors

Published on November 10th, 2021

Authors: Eduard V. Bocharov, Lothar Gremer, Anatoly S. Urban, Ivan S. Okhrimenko, Pavel E. VolynskyKirill D. Nadezhdin, Olga V. Bocharova, Daniil A. Kornilov, Yuliya A. Zagryadskaya, Anna V. Kamynina, Pavel K. Kuzmichev, Janine Kutzsche, Najoua Bolakhrif, Andreas Müller-Schiffmann, Norbert A. Dencher, Alexander S. Arseniev, Roman G. Efremov, Valentin I. Gordeliy, and Dieter Willbold

J. Med. Chem. 2021, 64, 22, 16464–16479. DOI:


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. AlldEnantiomeric 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.

Bocharov and co-workers 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.

InstrumentFluidity One-W
Therapeutic area: Amyloid, neurodegeneration

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