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一个基于性4-氨基的DNA编码的化学库,可以实现立体特异的异酶选择性蛋白质识别

Sebastian Oehler¹, Laura Lucaroni¹, Francesca Migliorini¹

¹Philochem AG, Otelfingen, Switzerland.

Nature chemistry

|July 3, 2023

概括

在DNA编码的化学库 (DEL) 中使用立体化学定义的支架显著增强了针对特定蛋白质标的连接体发现. 这种方法提高了选择性,导致了潜在的癌症疗法.

科学领域:

药用化学医学化学
化学生物学化学生物学
药物发现药物发现药物发现

背景情况:

用DNA编码的化学库 (DEL) 能够进行大规模的化合物选,但由于低效的目标相互作用而受到限制.
在DELs中的构建块的空间布局极大地影响了连接体结合和选择性.
制定提高DEL查生产率和带特异性的策略对于药物发现至关重要.

研究的目的:

调查DEL中的刚性,立体定义的中央支架是否可以改善连接体发现和标选择性.
为了合成和选基于4-aminopyrrolidine-2-carboxylic acid的立体异构体的DEL.
评估立体化学对连接体亲和力和对蛋白质标及其异型的选择性的影响.

主要方法:

合成一个DNA编码的化学库 (DEL),拥有3,735,936名成员,使用4-aminopyrrolidine-2-carboxylic acid的四个立体异构体作为支架.
通过比较选择,选DEL与药学相关的蛋白质标及其密切相关的异型.
击中验证和对联体亲和力和立体同位素特异性结合的分析.

主要成果:

中央支架的立体化学对联体亲属性产生了重大影响,在立体同位素之间观察到实质性的差异.
针对多个蛋白质标的强效和异酶选择性配体的识别.
发现选择性对瘤相关抗原的配体,证明了瘤选择性向 in vitro 和 in vivo.

结论:

使用立体定义的中央支架构建DEL可以提高图书馆的生产力和连接体选择性.
这一策略有助于发现能够在密切相关的蛋白质标之间进行区分的高度特异性的配体.
立体化学定义的DEL代表了识别选择性治疗方法的强大方法,包括针对癌症的选择性治疗方法.

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