一个紧的重编程的遗传代码,用于新发现蛋白质稳定性
Alexander A Vinogradov1, Yue Zhang1, Keisuke Hamada2
1Department of Chemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Journal of the American Chemical Society
|March 16, 2024
概括
这项研究引入了一个重编程的mRNA显示平台,用于发现代谢稳定的. 这种新方法利用非蛋白质氨基酸,提高了药物发现潜力.
科学领域:
- 生物化学
- 自然产品化学
- 药物发现
背景情况:
- 是具有生物工程潜力的复杂天然产品.
- 由于蛋白质生成氨基酸的使用,现有的硫发现平台产生了代谢不稳定的化合物.
研究的目的:
- 重新开发一种硫/mRNA显示平台,以发现代谢稳定的硫.
- 为了提高稳定性,将非蛋白质氨基酸纳入类结构.
主要方法:
- 在mRNA显示库中使用紧的重编程遗传代码.
- 对Traf2和NCK相互作用激酶 (TNIK) 进行了亲和选择.
- 确定了类的亲和力 (K_D) 和激酶抑制活性 (IC_50).
主要成果:
- 发现主要由非蛋白质性结构元素组成的.
- 鉴定了与TNIK高亲和度的结合剂 (最佳K_D=2.1nM),具有激酶抑制活性 (最佳IC_50=0. 15μM).
- 在人血清中达到高代谢稳定性 (半衰期高达99小时),含有多达15种非蛋白质氨基酸.
结论:
- 重新编程的平台可以发现具有显著改善的代谢稳定性的.
- 非蛋白质构建块有助于目标接触和独特的折叠形状.
- 这一进步对于早期药物发现应用, 需要稳定的治疗候选药物至关重要.
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