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首页> 外文期刊>ACS Omega >Identification of a New Function of Cardiovascular Disease Drug 3-Morpholinosydnonimine Hydrochloride as an Amyloid-β Aggregation Inhibitor
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Identification of a New Function of Cardiovascular Disease Drug 3-Morpholinosydnonimine Hydrochloride as an Amyloid-β Aggregation Inhibitor

机译：心血管疾病药物3-Morpholinosydnonimine Hydrochloride作为淀粉样β聚集抑制剂的新功能的鉴定。

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Cardiovascular disease (CVD) and Alzheimer’s disease (AD) have a mutual cause-and-effect relationship, and they share some common risk factors. Although numerous Food and Drug Administration (FDA)-approved drugs have been developed for CVD treatment, no drugs are clinically available for AD treatment. Given the common disease-causing factors and links between the two diseases and the well-demonstrated drugs for CVD, we propose to re-examine the new potential of the existing CVD drugs as amyloid-β (Aβ) inhibitors. 3-Morpholinosydnonimine hydrochloride (SIN-1) is an FDA-approved drug for inhibiting platelet aggregation in CVD. Herein, we examine the inhibition activity of SIN-1 on the aggregation and toxicity of Aβ_(1–42) using combined experimental and computational approaches. Collective experimental data from ThT, circular dichroism, and atomic force microscopy demonstrate that SIN-1 can effectively inhibit amyloid formation at every stage of Aβ aggregation by prolonging lag phase, slowing down aggregation rate, and reducing final fibril formation. The cell viability assay also shows that SIN-1 enables the protection of SH-SY5Y cells from Aβ-induced cell toxicity. Such an inhibition effect is attributed to interference with the structural transition of Aβ toward a β-sheet structure by SIN-1. Furthermore, molecular dynamic simulations confirm that SIN-1 preferentially binds to the C-terminal β-sheet grooves of an Aβ oligomer and consequently disrupts the β-sheet structure of Aβ and Aβ–Aβ association, explaining experimental observations. This work discovers a new function of SIN-1, making it a promising compound with dual protective roles in inhibiting both platelet and Aβ aggregations against CVD and AD.
机译：心血管疾病（CVD）和阿尔茨海默氏病（AD）具有互为因果关系，它们具有一些共同的危险因素。尽管已经开发了许多获得美国食品和药物管理局（FDA）批准的用于CVD治疗的药物，但临床上尚无可用于AD治疗的药物。考虑到常见的致病因素以及这两种疾病之间的联系以及经过充分证明的CVD药物，我们建议重新检查现有CVD药物作为β-淀粉样蛋白（Aβ）抑制剂的新潜力。 3-Morpholinosydnonimine hydrochloride（SIN-1）是FDA批准的抑制CVD中血小板聚集的药物。在这里，我们结合实验和计算方法研究了SIN-1对Aβ_（1-42）的聚集和毒性的抑制活性。来自ThT，圆二色性和原子力显微镜的集体实验数据表明，SIN-1可以通过延长迟滞期，减慢聚集速率并减少最终的原纤维形成来有效抑制Aβ聚集每个阶段的淀粉样蛋白形成。细胞活力测定还表明，SIN-1能够保护SH-SY5Y细胞免受Aβ诱导的细胞毒性的影响。这种抑制作用归因于SIN-1干扰Aβ向β-折叠结构的结构转变。此外，分子动力学模拟证实SIN-1优先与Aβ低聚物的C末端β-折叠槽结合，因此破坏了Aβ和Aβ-Aβ缔合的β-折叠结构，解释了实验观察。这项工作发现了SIN-1的新功能，使其成为一种有前途的化合物，在抑制血小板和Aβ聚集物上具有针对CVD和AD的双重保护作用。

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