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

Journal of Medicinal Chemistry. 2021. Vol. 64. No. 22. P. 16464–16479.

Bocharov E. V., Gremer L., Urban A. S., Okhrimenko I. S., Volynsky P. E., Nadezhdin K. D., Bocharova O. V., Kornilov D. A., Zagryadskaya Y. A., Kamynina A. V., Kuzmichev P. K., Kutzsche J., Bolakhrif N., Müller-Schiffmann A., Dencher N. A., Arseniev A. S., Efremov R., Gordeliy V. I., Willbold D.

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.

Keywords: молекулярное моделирование, molecular modeling, membrane protein, NMR spectroscopy, болезнь Альцгеймера, Peptide-Membrane Interactions, взаимодействия пептид-мембрана, Alzheimer´s disease, спектроскопия ЯМР, мембранные белок

Publication based on the results of: Supercomputer technologies for atomistic modeling of physical processes in condensed matter (2021)