Rationally designed peptidomimetic modulators of aβ toxicity in Alzheimer's disease.
Rationally designed peptidomimetic modulators of aβ toxicity in Alzheimer's disease.
复制标题
Aβ毒性在阿尔茨海默氏病中的合理设计的肽瘤调节剂。
DOI：
10.1038/srep08139
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发表时间：
2015-01-30
影响因子：
4.6
通讯作者：
Govindaraju T
中科院分区：
文献类型：
--
作者：
Rajasekhar K;Suresh SN;Manjithaya R;Govindaraju T
阿尔茨海默病是21世纪人类面临的毁灭性疾病之一。阿尔茨海默病的主要致病事件被认为是β-淀粉样蛋白(Aβ)多肽聚集成有毒聚集体。干扰这一过程的分子可能会作为治疗药物来治疗这种疾病。使用基于识别单元的多肽模拟物作为抑制剂是一种很有前途的方法，因为与天然多肽相比，它们表现出更好的蛋白酶稳定性。在这里，我们介绍了基于已知结合Aβ聚集体的KLvff(P1)序列设计的Aβ聚集体的模拟肽抑制剂。我们通过在N端(P2和P3)引入多个氢键供体-受体部分(胸腺嘧啶/巴比妥酸盐)来提高P1的抑制效率，并通过在交替位置(P4和P5)引入肌氨酸(N-甲基甘氨酸)单元来修饰骨架来提高血清的稳定性。硫代黄素测定、圆二色谱(CD)和显微镜观察表明，所合成的多肽类化合物对Aβ聚集体的抑制和溶解均表现出中等到良好的活性。在显示Aβ毒性的酵母细胞模型中研究了P4和P5的活性。P4和P5能将酵母细胞从Aβ毒害中解救出来，并通过自噬过程清除Aβ聚集体。
Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21st century. The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the β-amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process may act as therapeutic agents for the treatment of the disease. Use of recognition unit based peptidomimetics as inhibitors are a promising approach, as they exhibit greater protease stability compared to natural peptides. Here, we present peptidomimetic inhibitors of Aβ aggregation designed based on the KLVFF (P1) sequence that is known to bind Aβ aggregates. We improved inhibition efficiency of P1 by introducing multiple hydrogen bond donor-acceptor moieties (thymine/barbiturate) at the N-terminal (P2 and P3), and blood serum stability by modifying the backbone by incorporating sarcosine (N-methylglycine) units at alternate positions (P4 and P5). The peptidomimetics showed moderate to good activity in both inhibition and dissolution of Aβ aggregates as depicted by thioflavin assay, circular dichroism (CD) measurements and microscopy (TEM). The activity of P4 and P5 were studied in a yeast cell model showing Aβ toxicity. P4 and P5 could rescue yeast cells from Aβ toxicity and Aβ aggregates were cleared by the process of autophagy.
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