Microtubules, one of the major components of the cytoskeleton, play important roles as pathways for neuronal transport of cellular traffic. The loss of structural stability of microtubules causes detrimental effects on neurons and may contribute to several neurodegenerative diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, etc. The triazolopyrimidine class compound cevipabulin is a synthetic microtubule-stabilizing agent that has recently emerged as a drug for the treatment of Alzheimer’s disease. However, the mechanism of microtubule stabilization by cevipabulin has not yet been revealed. Here, we explored the effect of cevipabulin on stabilizing microtubules polymerized from purified tubulins in vitro. We observed the effects of the concentration of microtubule-stabilizing drugs, incubation time, and modification of the cevipabulin structure on the stabilization of microtubules in comparison to those of the most commonly used anticancer drug, paclitaxel. This study will provide insight into the action of cevipabulin in the treatment of neurodegenerative diseases. Stabilization of microtubules occurs by paclitaxel bound to the taxoid site and cevipabulin (and its derivative) bound to the taxoid site and/or vinca alkaloid domain of the β-tubulin in tubulin heterodimer.

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与抗癌药物西维布林和紫杉醇稳定微管的比较

微管是细胞骨架的主要组成部分之一，作为细胞交通的神经元运输途径发挥着重要作用。微管结构稳定性的丧失会对神经元造成不利影响，并可能导致多种神经退行性疾病，如阿尔茨海默病、肌萎缩侧索硬化、亨廷顿病等。 三唑并嘧啶类化合物 cevipabulin 是一种合成微管稳定剂，最近出现作为治疗阿尔茨海默病的药物。然而，cevipabulin 稳定微管的机制尚未揭示。在这里，我们探讨了 cevipabulin 对稳定体外纯化微管蛋白聚合的微管的影响。我们观察了微管稳定药物浓度、孵育时间、与最常用的抗癌药物紫杉醇相比，cevipabulin 结构的修饰对微管稳定性的影响。这项研究将深入了解 cevipabulin 在治疗神经退行性疾病中的作用。通过与紫杉醇位点结合的紫杉醇和与紫杉醇位点和/或微管蛋白异二聚体中β-微管蛋白的长春花生物碱结构域结合的西维帕布林（及其衍生物）来稳定微管。