TY  - JOUR
AU  - Bocharov, Eduard V.
AU  - Gremer, Lothar
AU  - Urban, Anatoly S.
AU  - Okhrimenko, Ivan S.
AU  - Volynsky, Pavel E.
AU  - Nadezhdin, Kirill D.
AU  - Bocharova, Olga V.
AU  - Kornilov, Daniil A.
AU  - Zagryadskaya, Yuliya A.
AU  - Kamynina, Anna V.
AU  - Kuzmichev, Pavel K.
AU  - Kutzsche, Janine
AU  - Bolakhrif, Najoua
AU  - Müller-Schiffmann, Andreas
AU  - Dencher, Norbert A.
AU  - Arseniev, Alexander S.
AU  - Efremov, Roman G.
AU  - Gordeliy, Valentin I.
AU  - Willbold, Dieter
TI  - All - d - Enantiomeric Peptide D3 Designed for Alzheimer’s Disease Treatment Dynamically Interacts with Membrane-Bound Amyloid-β Precursors
JO  - Journal of medicinal chemistry
VL  - 64
IS  - 22
SN  - 0022-2623
CY  - Washington, DC
PB  - ACS
M1  - FZJ-2022-00640
SP  - 16464 - 16479
PY  - 2021
N1  - Kein Post-print vorhanden
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:34739758
UR  - <Go to ISI:>//WOS:000754726000008
DO  - DOI:10.1021/acs.jmedchem.1c00632
UR  - https://juser.fz-juelich.de/record/905388
ER  -