Selecting Multitarget Peptides for Alzheimer's Disease.
Selecting Multitarget Peptides for Alzheimer's Disease.
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阿尔茨海默病的多靶点多肽选择
DOI：
10.3390/biom12101386
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发表时间：
2022-09-27
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
阿尔茨海默病(AD)是一种多因素疾病，发病机制复杂。开发多靶点药物可能是影响这种疾病认知功能进行性丧失的有力策略。本研究的目的是从中性粒细胞颗粒蛋白组织蛋白G衍生的一系列多肽变体中筛选出一个多靶点的先导肽候选。我们用以下标准筛选了8个候选多肽：(1)抑制和逆转淀粉样β(A-β)寡聚体，用酶联免疫吸附试验(ELISA)定量；(2)候选多肽与人晚期糖基化终产物受体(RAGE)、Toll样受体4(TLR4)和S100钙结合蛋白A9(S100A9)的直接结合；(3)对β寡聚体诱导的神经细胞死亡的保护作用，使用台盼蓝测量小鼠神经元细胞系的细胞死亡；(4)使用人TLR4报告细胞系，S100A9抑制TLR4的激活。我们选择了一种满足这四个标准的27聚体先导肽。这种先导肽是一种特权结构，显示出固有的多靶点活性。通过针对神经炎症和神经变性，这种多肽有望显著影响阿尔茨海默病小鼠模型的认知能力下降。
Alzheimer’s disease (AD) is a multifactorial disease with a complex pathogenesis. Developing multitarget drugs could be a powerful strategy to impact the progressive loss of cognitive functions in this disease. The purpose of this study is to select a multitarget lead peptide candidate among a series of peptide variants derived from the neutrophil granule protein cathepsin G. We screened eight peptide candidates using the following criteria: (1) Inhibition and reversion of amyloid beta (Aβ) oligomers, quantified using an enzyme-linked immunosorbent assay (ELISA); (2) direct binding of peptide candidates to the human receptor for advanced glycation end-products (RAGE), the Toll-like receptor 4 (TLR4) and the S100 calcium-binding protein A9 (S100A9), quantified by ELISA; (3) protection against Aβ oligomer-induced neuronal cell death, using trypan blue to measure cell death in a murine neuronal cell line; (4) inhibition of TLR4 activation by S100A9, using a human TLR4 reporter cell line. We selected a 27-mer lead peptide that fulfilled these four criteria. This lead peptide is a privileged structure that displays inherent multitarget activity. This peptide is expected to significantly impact cognitive decline in mouse models of Alzheimer’s disease, by targeting both neuroinflammation and neurodegeneration.
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