研究新药恢复变异蛋白,拯救基因组守卫者以对抗癌症

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一种称作p53 的蛋白,由于会发出杀死破坏DNA细胞的警告,并且防止其癌变,因此被称为”基因守卫者”。由于又大又软,以标准影像工具很难跟踪这个分子变形者。因此加州大学圣地牙哥分校运算生物学家Amaro转而利用超级电脑。她插入p53片段的新X光快照,加强程序,从而在百万分之一秒层面制作出该蛋白160万个原子中每个原子颤动的影像。Amaro不只对健康p53的行为感兴趣:她希望了解p53基因突变可能会导致的效应。

在数十个模拟中,她和同事追踪了普通p53突变如何使这个原本已经软踏踏的蛋白变得更加不稳定,他们使其扭曲并阻止其与DNA结合。另外一些模拟还显示他们可能与一种潜在药物合作,有时,该突变蛋白核心会形成一个小裂缝。当Amaro在模型中加入虚拟的药物分子之后,药物会停留在裂缝中,从而让p53变得足够稳定,恢复正常功能。研究人员激动地表示:”癌症生物学长久以来都梦想着一个找到可以恢复p53活性的小分子药物。”

美国每年有近170万人被诊断出癌症,其中百分之五十的人存在不同程度的p53基因突变,显示这个常规蛋白在预防癌症中的重要性,也是药厂高度关注的目标。但目前开发的数十个p53药物中,大多数药物只是在设法提高健康p53的水准。尽管这一领域的研究已经进行了数十年,但尚未有任何药物进入市场。

Amaro的工作展示了一些科学实验室和小公司利用新途径瞄准p53所取得的进展:在p53生病后拯救它。他们正在寻找能够与p53结合以及支撑变异p53蛋白的药物,从而使其恢复形状与功能,完成常规任务。其中一种药物已经通过初期人体安全试验,现在一项更加先进的临床试验正在欧洲进行。其他的潜在药物正在接近人体临床试验。如果临床上取得任何成功,它们将能显着改变癌症治疗的面貌,此外还包括其他错误折叠蛋白类疾病,甚至是阿兹海默症。

虽然恢复p53 并不容易,但相关研究的回馈相当可观,因为它不仅能够战略性地治疗多种癌症,而且只需要一些药物种类就足够了,特别是将其与诱导肿瘤细胞损伤并促使p53做出回应的化疗药物结合使用时。P53变异倾向于出现在该蛋白的核心,而该位点可决定蛋白与DNA结合并对其形状有着重要的影响。能够恢覆p53活性的药物不仅能对该蛋白的其中一种突变起作用,而是应对很多种基因突变。

对p53在镇压肿瘤方面神秘力量的了解,从1979年p53蛋白被发现之后开始,就已经展示p53在镇压肿瘤方面的力量。最初,它被认为是一种肿瘤,能够在一定条件下让一个细胞癌化。大约10年后,它被确认为可以与DNA相结合,并打开旨在治疗细胞损伤的其他基因表达。如果能够与p53互动的其他细胞分子较多,损害就比较广泛,它会触动p53发出让细胞自杀的信号。

目前已知这种蛋白可以控制且与数十种基因和蛋白互动,它有助于调节细胞生长和复制的分子活动周期。因为它的重要性,p53 在细胞中受到严格控制。因为另一个蛋白MDM2会纠缠到p53分子上并摧毁它们,并控制其数量。

不过这种控制机制可能会因为多种原因而失效。当p53 发生突变时,MDM2就不能再攻击它。因此,失效的p53蛋白会在未受控的状态下在细胞中积累,并让剩余的健康蛋白继续工作。如果没有这些”基因守卫”的巡视,癌症前期细胞就会存活并繁殖,最终变成完全恶性的肿瘤。

大多数瞄准p53的抗癌尝试均设法提高该蛋白水平。其中常见的方法是阻止MDM2及其亲属MDMX降低p53的水平。其希望是这样做会让一些尚未基因突变的p53存活时间更长,从而杀死有害细胞。目前Amaro和其他研究人员瞄准问题核心的变异p53。上世纪90年代,癌症细胞试管实验显示一些药物能恢复变异p53的正常功能,但它们并不能持续作用。结果表明,一种叫作CP-31398 不是直接恢复p 53,而是透过扰乱细胞的DNA 杀死它们。

1998年,研究人员对美国国家癌症研究所的2000种系列药物进行了检测,发现其中两种药物能够恢复p53的活性,杀死癌细胞。其中一种叫作MIRA-I,结果但它虽然能杀死癌细胞,可是也在实验小鼠体内存在毒性。另一种叫作PRIMA-1的药物能够分解为另一种叫作MQ的化合物。三年前,Amaro及其同事报告指出,电脑模型结果显示MQ被连接在突变p53核心内部形成的囊内。而这种药物能够支撑p53蛋白恢复形状,并拯救其功能。

虽然目前还不确定这是否为一种稳定p53 的策略,但它一旦成功,将会远远超过其他基因靶向疗法,对癌症治疗的影响将相当可观,每年造福数百万名癌症患者。未来某一天,它可能会向具有类似癌症迹象的人提供挽救p53的药物,使他们的细胞守卫者发现癌症迹象,并在其开始之前将其扫除。

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