Centre for the Environment, IIT Guwahati, Assam 781039, India.
Centre for the Environment, IIT Guwahati, Assam 781039, India; Department of Chemistry, IIT Guwahati, Assam 781039, India.
Bioorg Med Chem. 2021 Mar 1;33:116017. doi: 10.1016/j.bmc.2021.116017. Epub 2021 Jan 16.
Accumulation and deposition of misfolded amyloid β (Aβ) peptide outside the nerve cells are one of the major causes of Alzheimer's disease (AD). To date, one of the promising therapeutic strategies for AD is to block the early steps associated with the aggregation of Aβ peptide. We have developed synthetic breaker peptides derived from the original Aβ sequences that undergo self-cyclization in situ. We have focussed and replaced Val-18 (of Aβ) by side-chain modified glutamic acid (Glu-OBn) to generate adequate turn through in-situ peptide cyclization to disrupt the β-sheet structure of Aβ. The disruption of amyloid fibril formation and the mechanism of the 'inhibition of aggregation' were studied by various biophysical methods, such as ThT-assay, TEM, Congo-red birefringence study. CD and FTIR spectroscopy were used to characterize the conformational change during the aggregation process. Results suggest that designed breaker peptides may be useful to inhibit and disrupt not only Aβ peptide but related peptides that undergo aggregation.
淀粉样β（Aβ）肽在神经细胞外的错误折叠和沉积是阿尔茨海默病（AD）的主要原因之一。迄今为止，AD 有希望的治疗策略之一是阻断与 Aβ肽聚集相关的早期步骤。我们已经开发出源自原始 Aβ序列的合成断裂肽，这些肽在原位进行自环化。我们集中并取代了 Aβ 的 Val-18（Aβ的）通过侧链修饰的谷氨酸（Glu-OBn）生成足够的转角，通过原位肽环化破坏 Aβ的β-片层结构。通过各种生物物理方法研究了淀粉样纤维形成的破坏和“抑制聚集”的机制，例如 ThT 分析、TEM、刚果红双折射研究。CD 和 FTIR 光谱用于表征聚集过程中的构象变化。结果表明，设计的断裂肽不仅可能有助于抑制和破坏 Aβ肽，而且还可能有助于抑制和破坏经历聚集的相关肽。
