通过选择DNA编码的动态图书馆来发现蛋白质模板连接体
Yu Zhou1,2, Wenyin Shen1, Ying Gao1
1Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, China.
Nature chemistry
|February 7, 2024
概括
这项研究引入了一种新的蛋白质模板DNA编码动态库 (DEDL) 选择方法. 它可以识别完整的类似药物的分子,消除了药物发现过程中具有挑战性的断片连接步骤.
科学领域:
- 药用化学 医学化学
- 化学生物学 化学生物学
- 药物发现技术 药物发现技术
背景情况:
- 用DNA编码的化学库 (DEL) 是药物发现的强大工具.
- 双药 DEL 识别出协同作用的结合物,但需要难以进行选择后的链接.
- 现有的DEL方法往往需要具有挑战性的断片连接来实现完整的连接体合成.
研究的目的:
- 开发一种新的DNA编码动态库 (DEDL) 选择方法.
- 为了能够直接识别完整的配体/抑制剂结构.
- 克服当前DEL技术中碎片链接的局限性.
主要方法:
- 从DNA编码的动态库 (DEDL) 中选择蛋白质模板.
- 使用动态DNA杂交和目标模板的 in situ 配体合成.
- 在图书馆内整合和编码链接器结构,以便直接采样.
主要成果:
- 在没有选择后链接的情况下成功识别了完整的配体/抑制剂结构.
- 在435万和300万会员的DEDL中表现出了表现.
- 针对四种治疗相关的标蛋白实现了击中选择.
结论:
- 蛋白质模板DEDL方法通过直接产生完整的配体,简化了药物发现.
- 这种方法绕过了先前的双药孔DEL固有的具有挑战性的断片连接步骤.
- 开发的DEDL平台在识别新疗法方面显示出显著的前景.
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