Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP 208016, India.
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP 208016, India.
Int J Biol Macromol. 2023 Jun 1;239:124231. doi: 10.1016/j.ijbiomac.2023.124231. Epub 2023 Mar 28.
The cascade of amyloid formation relates to multiple complex events at the molecular level. Previous research has established amyloid plaque deposition as the leading cause of Alzheimer's disease (AD) pathogenesis, detected mainly in aged population. The primary components of the plaques are two alloforms of amyloid-beta (Aβ), Aβ and Aβ peptides. Recent studies have provided considerable evidence contrary to the previous claim indicating that amyloid-beta oligomers (AβOs) as the main culprit responsible for AD-associated neurotoxicity and pathogenesis. In this review, we have discussed the primary features of AβOs, such as assembly formation, the kinetics of oligomer formation, interactions with various membranes/membrane receptors, the origin of toxicity, and oligomer-specific detection methods. Recently, the discovery of rationally designed antibodies has opened a gateway for using synthesized peptides as a grafting component in the complementarity determining region (CDR) of antibodies. Thus, the Aβ sequence motif or the complementary peptide sequence in the opposite strand of the β-sheet (extracted from the Protein Data Bank: PDB) helps design oligomer-specific inhibitors. The microscopic event responsible for oligomer formation can be targeted, and thus prevention of the overall macroscopic behaviour of the aggregation or the associated toxicity can be achieved. We have carefully reviewed the oligomer formation kinetics and associated parameters. Besides, we have depicted a thorough understanding of how the synthesized peptide inhibitors can impede the early aggregates (oligomers), mature fibrils, monomers, or a mixture of the species. The oligomer-specific inhibitors (peptides or peptide fragments) lack in-depth chemical kinetics and optimization control-based screening. In the present review, we have proposed a hypothesis for effectively screening oligomer-specific inhibitors using the chemical kinetics (determining the kinetic parameters) and optimization control strategy (cost-dependent analysis). Further, it may be possible to implement the structure-kinetic-activity-relationship (SKAR) strategy instead of structure-activity-relationship (SAR) to improve the inhibitor's activity. The controlled optimization of the kinetic parameters and dose usage will be beneficial for narrowing the search window for the inhibitors.
淀粉样蛋白形成的级联反应与分子水平上的多个复杂事件有关。先前的研究已经确定淀粉样斑块沉积是阿尔茨海默病（AD）发病机制的主要原因，主要在老年人群中检测到。斑块的主要成分是两种淀粉样β（Aβ）同种型，即 Aβ 和 Aβ 肽。最近的研究提供了相当多的证据，与之前的说法相反，表明淀粉样β 寡聚物（AβOs）是导致 AD 相关神经毒性和发病机制的主要罪魁祸首。在这篇综述中，我们讨论了 AβOs 的主要特征，如组装形成、寡聚物形成的动力学、与各种膜/膜受体的相互作用、毒性的起源以及寡聚体特异性检测方法。最近，合理设计的抗体的发现为使用合成肽作为抗体互补决定区（CDR）中的嫁接成分开辟了一条道路。因此，Aβ 序列基序或β-折叠相反链上的互补肽序列（从蛋白质数据库：PDB 中提取）有助于设计寡聚体特异性抑制剂。可以针对负责寡聚体形成的微观事件进行靶向，从而可以防止聚集的整体宏观行为或相关毒性。我们仔细审查了寡聚体形成动力学和相关参数。此外，我们详细描述了如何理解合成肽抑制剂可以阻止早期聚集物（寡聚体）、成熟原纤维、单体或它们的混合物。寡聚体特异性抑制剂（肽或肽片段）缺乏深入的化学动力学和基于优化控制的筛选。在本综述中，我们提出了一个假设，即使用化学动力学（确定动力学参数）和优化控制策略（成本相关分析）有效地筛选寡聚体特异性抑制剂。此外，可能可以实施结构-动力学-活性关系（SKAR）策略来代替结构-活性关系（SAR）来提高抑制剂的活性。动力学参数和剂量使用的受控优化将有利于缩小抑制剂的搜索窗口。
