摘要
背景:抗聚集药物在阿尔茨海默病的治疗方法中起着重要作用。我们已经开发出了一些能够抑制tau蛋白的病理聚集的化合物。应用程序的一个常见障碍是穿过细胞膜的有限的渗透进入细胞,其中tau蛋白聚集发生在细胞质中。我们用一种诱导N2a细胞表达tau蛋白和tau蛋白聚集体的重复结构域和发展。 目的:合成了几种多肽聚合物缀合物,以提高化合物在细胞内的吸收,从而提高其生物医学应用。本研究的目的是测试肽抑制剂复合物是否仍然保持tau蛋白聚集的抑制活性。 方法:将筛选出的肽序列与高结合容量的聚合抑制剂的一个子集并确定了它们的荧光显微镜和MALDI质谱在药物的溶解度和有效的肤色。探讨合成配合物对tau蛋白聚集倾向的影响。通过测量细胞凋亡标志来研究毒性的影响。 结果/结论:肽复合物的测试没有显示在总tau蛋白的水平下降,但溶于pelletable tau蛋白的种类的比例下降。这表明不溶性tau低聚物转化成可溶的形式,似乎比不溶性的毒性小,可见凋亡细胞的减少。因此,由于提高了药物的生物利用度,肽复合物比单独的化合物具有更高的效力。
关键词: 阿尔茨海默病,生物,组合筛选,tau蛋白,细胞模型,聚集调制器,丹宁。
Current Alzheimer Research
Title:Inhibition of Tau Protein Aggregation by Rhodanine-based Compounds Solubilized Via Specific Formulation Additives to Improve Bioavailability and Cell Viability
Volume: 14 Issue: 7
关键词: 阿尔茨海默病,生物,组合筛选,tau蛋白,细胞模型,聚集调制器,丹宁。
摘要: Background: Anti-aggregation drugs play an important role in therapeutic approaches for Alzheimer’s disease. We have previously developed a number of compounds that are able to inhibit the pathological aggregation of Tau protein. One common obstacle to application is the limited penetration across the plasma membranes into cells, where Tau aggregation occurs in the cytosol. We used an inducible N2a cell line which expresses the repeat domain of tau and develops tau aggregates.
Objective: Several peptide-polymer conjugates were synthesized to enhance the uptake of compounds into cells and thus to improve their biomedical application. The aim of this study was to test whether the peptide-inhibitor complexes still retain their inhibitory activity on Tau aggregation. Method: We screened peptide sequences with high binding capacity to a subset of aggregation inhibitors and identified them by fluorescence microscopy and MALDI MS/MS with regard to drug solubility and effective complexion. To explore whether the synthesized complexes can influence the aggregation propensity of Tau we performed in vitro and cellular assays. The effect on toxicity was investigated by measuring apoptosis markers. Results/Conclusion: The tested peptide-compound complexes show no decrease in the total Tau levels but decreased ratios of soluble to pelletable Tau species. This indicates a conversion of insoluble Tau oligomers into soluble forms which appear to be less toxic than the insoluble ones, as seen by a decrease of apoptotic cells. Thus the peptide-compound complexes have a higher potency than the compounds alone due to improved bioavailability of the drug.Export Options
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Cite this article as:
Inhibition of Tau Protein Aggregation by Rhodanine-based Compounds Solubilized Via Specific Formulation Additives to Improve Bioavailability and Cell Viability, Current Alzheimer Research 2017; 14 (7) . https://dx.doi.org/10.2174/1567205014666170202103136
DOI https://dx.doi.org/10.2174/1567205014666170202103136 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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