蛋白酶稳定配体控制淀粉样β肽聚集和毒性

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2023-02-15 DOI:10.1021/acsbiomedchemau.2c00067
Rathnam Mallesh,  Juhee khan, Prabir Kumar Gharai, Varsha Gupta, Rajsekhar Roy and Surajit Ghosh*, 
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引用次数: 0

摘要

可溶性淀粉样蛋白β(Aβ)肽聚合成蛋白酶稳定的不溶性原纤维聚集体是阿尔茨海默病(AD)发病机制的关键步骤。N-末端(NT)疏水性中心结构域片段16KLVFF20通过自识别母体Aβ肽,然后在AD大脑中聚集Aβ,在β片的形成和稳定中发挥重要作用。在这里,我们分析了NT区域通过天然Aβ肽片段中的单个氨基酸突变诱导Aβ肽中β-片形成的作用。我们利用天然aβ肽片段(KLVFFAE)中的疏水残基亮氨酸和脯氨酸,在18Val处单突变设计了14种疏水肽(NT-01至NT-14),并分析了其对aβ聚集体形成的影响。在所有这些肽中,NT-02、NT-03和NT-13显著影响Aβ聚集体的形成。当NT肽与Aβ肽共孵育时,观察到Aβ的β-片形成显著减少,无规卷曲含量增加,这通过圆二色光谱和傅里叶变换红外光谱得到证实,然后通过硫黄素-T(ThT)结合测定测量原纤维形成减少。通过刚果红和ThT染色以及电子显微镜检查来监测聚集抑制。此外,NT肽在体外保护PC-12分化的神经元免受Aβ诱导的毒性和细胞凋亡的影响。因此,用促进无规螺旋构象的蛋白酶稳定配体操纵Aβ二级结构可能为控制AD患者中观察到的Aβ聚集体提供了一种工具。
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Controlling Amyloid Beta Peptide Aggregation and Toxicity by Protease-Stable Ligands

Polymerization of soluble amyloid beta (Aβ) peptide into protease-stable insoluble fibrillary aggregates is a critical step in the pathogenesis of Alzheimer’s disease (AD). The N-terminal (NT) hydrophobic central domain fragment 16KLVFF20 plays an important role in the formation and stabilization of β-sheets by self-recognition of the parent Aβ peptide, followed by aggregation of Aβ in the AD brain. Here, we analyze the effect of the NT region inducing β-sheet formation in the Aβ peptide by a single amino acid mutation in the native Aβ peptide fragment. We designed 14 hydrophobic peptides (NT-01 to NT-14) by a single mutation at 18Val by using hydrophobic residues leucine and proline in the natural Aβ peptide fragment (KLVFFAE) and analyzed its effect on the formation of Aβ aggregates. Among all these peptides, NT-02, NT-03, and NT-13 significantly affected the Aβ aggregate formation. When the NT peptides were coincubated with the Aβ peptide, a significant reduction in β-sheet formation and increment in random coil content of Aβ was seen, confirmed by circular dichroism spectroscopy and Fourier transform infrared spectroscopy, followed by the reduction of fibril formation measured by the thioflavin-T (ThT) binding assay. The aggregation inhibition was monitored by Congo red and ThT staining and electron microscopic examination. Moreover, the NT peptides protect the PC-12 differentiated neurons from Aβ-induced toxicity and apoptosis in vitro. Thus, manipulation of the Aβ secondary structure with protease-stable ligands that promote the random coil conformation may provide a tool to control the Aβ aggregates observed in AD patients.

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ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
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期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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