结合片和天然产品碎片的宏循环方式
Stéphanie M Guéret1,2, Sasikala Thavam3, Rodrigo J Carbajo4
1Department of Chemical Biology, AstraZeneca-Max Planck Institute Satellite Unit, Max-Planck-Institute of Molecular Physiology, 44227 Dortmund, Germany.
Journal of the American Chemical Society
|February 15, 2020
概括
研究人员开发了PepNats, 这是一种使用自然产品启发的结构来模仿"热环"蛋白质段的新方法. 这种方法为向蛋白相互作用创造了结构约束的,从而产生了新的治疗候选物.
科学领域:
- 医学化学
- 结构生物学
- 生物化学
背景情况:
- "热环"蛋白质段由于它们的可变结构,对蛋白质与蛋白质相互作用至关重要.
- 模仿这些动态区域是一个挑战, 但对于药物发现至关重要.
研究的目的:
- 引入一种新的模式,PepNats,用于创建受制约的蛋白质模仿"热环".
- 来自可诱导的氧化合成酶 (iNOS) 和人类相关蛋白 (AGRP) 热环的PepNats的合成和特征.
- 评估这些PepNats与各自的生物标的结合亲和性和选择性.
主要方法:
- 将自然产品 (NP) 启发的结构纳入宏环.
- 通过 imine 形成使用宏循环的固体相合成.
- 用于构造约束的立体选择性1,3-二极循环加法.
主要成果:
- 从iNOS和AGRP热环中成功合成了宏环PepNats.
- 来自iNOS的PepNats对含有SPRY域的SOCS盒蛋白2 (SPSB2) 显示出强大的配体活性.
- 来自AGRP的PepNats对黑色皮质素 (MC) 受体表现出选择性的配体活性.
结论:
- 基于NP的断片的绝对配置决定了的构造和结合特性.
- 将NP支架与性表位结合起来,可以产生有效的热循环模拟.
- PepNats代表了开发具有治疗潜力的结构约束的有前途的策略.
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