Accepted_test

Molecular interactions of β-amyloid peptides, as disordered proteins, and promising drugs based on all-D-enantiomeric peptides
by Bocharov E.V. | Okhrimenko I.S. | Volynsky P.E. | Pavlov K.V. | Zlobina V.V. | Bershatsky Ya.V. | Kryuchkova A.K. | Kuzmichev P.K. | Efremov R.G. | Moscow Institute of Physics and Technology; Shemyakin–Ovchinnikov Institute of bioorganic chemistry RAS | Moscow Institute of Physics and Technology | Shemyakin–Ovchinnikov Institute of bioorganic chemistry RAS | Moscow Institute of Physics and Technology | Moscow Institute of Physics and Technology | Moscow Institute of Physics and Technology; Shemyakin–Ovchinnikov Institute of bioorganic chemistry RAS | Moscow Institute of Physics and Technology | Moscow Institute of Physics and Technology | Moscow Institute of Physics and Technology; Shemyakin–Ovchinnikov Institute of bioorganic chemistry RAS
Abstract ID: 698
Event: BGRS-abstracts
Sections: [Sym 3] Section “Pharmacology cheminformatics and chemical biology”

Alzheimer's disease (AD) is a devastating neurodegenerative disease that leads to severe dementia. Detailed information on the structure, dynamics and intermolecular interactions of biomolecules directly involved in the development of Alzheimer's disease is necessary for the rational development of new biologically active compounds and screening of existing ones in order to obtain the most effective drug candidates. Genetic evidence strongly suggests that aberrant production, aggregation, and/or clearance of neurotoxic amyloid-β (Aβ) peptides, being the products of sequential cleavage of transmembrane amyloid precursor protein (APP), triggers disease. All-D-enantiomeric peptide D3 and its derivatives were recently selected using phage display for direct destruction of cytotoxic Aβ aggregates. Currently, one of the D3-like compounds is about to enter phase II clinical trials. We present experimental evidence showing that D3-peptide, being an intrinsically disordered peptide (IDP), can dynamically and specifically bind in IDP/IDP-like manner to the extracellular juxtamembrane region of membrane-bound Aβ precursor, CTFβ transmembrane fragment of amyloid precursor protein (APP672-726, Aβ1-55 in amyloid-β numeration). The data suggest that D-enantiomeric peptide D3 recognizes the amyloidogenic region of APP and its fragments - Аβ peptides, restricting conformational diversity not compromising its α-helicity and preventing intermolecular hydrogen bond formation, which would create prerequisites for inhibition of early steps of Aβ conversion into β-conformation and its toxic oligomerization associated with early stages of AD development. The achieved progress in understanding the molecular mechanism of D3-peptide action is an important step towards development of an effective AD treatment and prevention strategy.