Research Center for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology (State University), 141701 Dolgoprudny, Russia.
Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia.
J Med Chem. 2021 Nov 25;64(22):16464-16479. doi: 10.1021/acs.jmedchem.1c00632. Epub 2021 Nov 5.
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. 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.
阿尔茨海默病（AD）是一种严重的神经退行性疾病，目前尚无已知的有效治疗方法。有毒的淀粉样β肽（Aβ）寡聚体在 AD 的发病机制中起着关键作用。AlldEnantiomeric 肽 D3 及其衍生物的开发旨在分解和破坏细胞毒性 Aβ 聚集物。其中一种 D3 类似物正在进入 II 期临床试验；然而，其预防疾病或药理学作用的高分辨率细节尚不完全清楚。我们证明，肽 D3 稳定 Aβ单体与含有 Aβ序列的淀粉样前体蛋白膜结合片段的细胞外近膜区动态相互作用。基于 NMR 测量结果的 MD 模拟表明，D3 靶向淀粉样形成区域，不损害其α-螺旋性并防止分子间氢键形成，从而为抑制 Aβ转化为β构象及其毒性寡聚化的早期步骤创造了前提条件。对 D3 作用分子机制的深入了解有助于开发有效的 AD 治疗和预防策略。
