Theodoropoulou Marilena K, Vraila Konstantina D, Papandreou Nikos C, Nasi Georgia I, Iconomidou Vassiliki A
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 157 01 Athens, Greece.
Biomolecules. 2024 Dec 30;15(1):28. doi: 10.3390/biom15010028.
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by extracellular amyloid plaques, predominantly consisting of amyloid- (A) peptides. The oligomeric form of A is acknowledged as the most neurotoxic, propelling the pathological progression of AD. Interestingly, besides A, other proteins are co-localized within amyloid plaques. Peptide analogs corresponding to the "aggregation-prone" regions (APRs) of these proteins could exhibit high-affinity binding to A and significant inhibitory potential against the A oligomerization process. The peptide analogs of co-localized protease, Cathepsin B, may act as such potent inhibitors. In silico studies on the complexes of the oligomeric state of A and Cathepsin B peptide analogs were performed utilizing molecular docking and molecular dynamics simulations, revealing that these analogs disrupt the -sheet-rich core of A oligomers, a critical structural feature of their stability. Of the four peptide analogs evaluated, two demonstrated considerable potential by effectively destabilizing oligomers while maintaining low self-aggregation propensity, i.e., a crucial consideration for therapeutic safety. These findings point out the potential of APR-derived peptide analogs from co-localized proteins as innovative agents against AD, paving the way for further exploration in peptide-based therapeutic development.
阿尔茨海默病（AD）是一种复杂的神经退行性疾病，其特征为细胞外淀粉样斑块，主要由淀粉样β（Aβ）肽组成。Aβ的寡聚体形式被认为是最具神经毒性的，推动了AD的病理进展。有趣的是，除了Aβ之外，其他蛋白质也共定位于淀粉样斑块内。与这些蛋白质的“易于聚集”区域（APR）相对应的肽类似物可能表现出与Aβ的高亲和力结合以及对Aβ寡聚化过程的显著抑制潜力。共定位蛋白酶组织蛋白酶B的肽类似物可能充当此类强效抑制剂。利用分子对接和分子动力学模拟对Aβ寡聚体状态与组织蛋白酶B肽类似物的复合物进行了计算机模拟研究，结果表明这些类似物破坏了Aβ寡聚体富含β折叠的核心，这是其稳定性的关键结构特征。在评估的四种肽类似物中，有两种通过有效破坏寡聚体同时保持低自聚集倾向而显示出相当大的潜力，即治疗安全性的关键考虑因素。这些发现指出了来自共定位蛋白质的APR衍生肽类似物作为抗AD创新药物的潜力，为基于肽的治疗开发的进一步探索铺平了道路。
