%0 Journal Article
%A Bocharov, Eduard V.
%A Gremer, Lothar
%A Urban, Anatoly S.
%A Okhrimenko, Ivan S.
%A Volynsky, Pavel E.
%A Nadezhdin, Kirill D.
%A Bocharova, Olga V.
%A Kornilov, Daniil A.
%A Zagryadskaya, Yuliya A.
%A Kamynina, Anna V.
%A Kuzmichev, Pavel K.
%A Kutzsche, Janine
%A Bolakhrif, Najoua
%A Müller-Schiffmann, Andreas
%A Dencher, Norbert A.
%A Arseniev, Alexander S.
%A Efremov, Roman G.
%A Gordeliy, Valentin I.
%A Willbold, Dieter
%T All - d - Enantiomeric Peptide D3 Designed for Alzheimer’s Disease Treatment Dynamically Interacts with Membrane-Bound Amyloid-β Precursors
%J Journal of medicinal chemistry
%V 64
%N 22
%@ 0022-2623
%C Washington, DC
%I ACS
%M FZJ-2022-00640
%P 16464 - 16479
%D 2021
%Z Kein Post-print vorhanden
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:34739758
%U <Go to ISI:>//WOS:000754726000008
%R 10.1021/acs.jmedchem.1c00632
%U https://juser.fz-juelich.de/record/905388