Science:用人造蛋白质来设计疫苗,其前景极其广阔

2020-05-17 Lauren 转化医学网

导言:重新设计蛋白质的最终目的是创造具有新生物学功能的蛋白质。从结构的角度来看,这仍然是一个挑战,因为天然蛋白质中的大多数生物功能是由不规则和不连续的结构基序介导的。相比之下,最新的蛋白质设计技术在设

导言:重新设计蛋白质的最终目的是创造具有新生物学功能的蛋白质。从结构的角度来看,这仍然是一个挑战,因为天然蛋白质中的大多数生物功能是由不规则和不连续的结构基序介导的。相比之下,最新的蛋白质设计技术在设计高度规则的结构方面表现突出。因此,迄今为止设计的大多数从头开始蛋白质要么是无功能的,要么是由规则的、连续的二级结构编码的现有功能。重新设计蛋白的一个有希望的应用是在疫苗设计中,更具体地说是在天然蛋白的环境之外来模拟病毒表位的蛋白质的设计。

疫苗是预防传染病传播最有效的干预手段之一。疫苗可以触发免疫系统产生抗体,从而保护身体免受感染。然而,如流感或登革热等许多重要的病原体,现在依然仍然缺乏有效的疫苗。

EPFL工程学院蛋白质设计与免疫工程实验室(LPDI)的教授布鲁诺·科雷亚(Bruno Correia)表示,“当疫苗不起作用时,我们倾向于认为这是因为产生的抗体没有保护作用,这通常是因为我们的免疫系统产生了错误的抗体。”科雷亚实验室的科学家们现在已经开发出一种设计人工蛋白质的策略,这种蛋白质可以非常精确地指示身体的免疫系统产生哪些抗体。这项研究在5月15日发表在《科学》杂志上。

像搭乐高积木一样构建蛋白质
EPFL团队利用计算方法设计了人造蛋白质。该研究的联合主要作者、博士生车阳(Che Yang)表示,“它们在自然界中并不存在。”

该论文的合著者法比安·西斯特伦(Fabian Sesterhenn)说,“我们开发了一种名为TopoBuilder的蛋白质设计算法。它可以让你构建蛋白质,就像把乐高积木放在一起一样。组装具有新功能的人造蛋白质绝对是一件令人着迷的事情。”这些蛋白质作为免疫原,在体内诱导靶向病毒中和抗体(nAbs)方面显示出良好的前景。迄今为止,以表位为中心的免疫原仅限于规则且连续的单个表位,极大地限制了它们在疫苗设计领域的潜力。

没有疫苗的疾病
科雷亚的团队专注于设计新的蛋白质,这种蛋白质可以产生呼吸道合胞病毒(RSV)疫苗。呼吸道合胞病毒会引起严重的肺部感染,是婴幼儿和老年人住院治疗的主要原因。科雷亚表示:“尽管经过几十年的研究,到目前为止,还没有针对呼吸道合胞病毒的疫苗或治疗方法。”

人工蛋白在实验室中产生,然后在动物模型中进行测试,并触发免疫系统产生针对RSV弱点的特异性抗体。”科雷亚说:“我们的发现鼓舞人心,因为它们表明,有一天,我们将能够通过促使免疫系统产生这些特定抗体,设计出更有效地针对特定病毒的疫苗。我们还有很多工作要做,以使我们开发的疫苗更有效,这项研究是朝着这个方向迈出的第一步。”

新蛋白的制备方法不仅具有免疫学的应用,还可以用于生物技术的各个分支,以扩大天然蛋白的结构和功能范围。西斯特伦表示,“我们现在可以使用蛋白质设计工具为其他生物医学应用创造蛋白质,如基于蛋白质的药物或功能化生物材料。”

这项工作为新蛋白的功能化提供了一条新的途径,并为以表位为中心的疫苗设计提供了一个蓝图,为原始抗体和启动抗体库中诱导的抗体特异性提供了前所未有的控制水平。除了免疫原之外,设计具有高结构复杂度的功能位点的新生蛋白的能力将广泛应用于扩展结构和序列库,但最重要的是,天然蛋白质的前景很广阔。

原始出处:

Fabian Sesterhenn, Che Yang, Jaume Bone, et.al. De novo protein design enables the precise induction of RSV-neutralizing antibodies. Science 15 May 2020: Vol. 368, Issue 6492, eaay5051

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    2020-05-19 jichang

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美国制药巨头辉瑞(Pfizer)开始进行新冠肺炎疫苗的试验性人体测试。

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山东的袁先生家里有个10个月的宝宝,孩子出生后每个月都要进行的疫苗接种程序被新冠疫情打乱了。