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采用类酶的非自然乱交来构建类宏循环库,用于连接体的发现

Yan-Ni Zhang¹, Xiao-Cui Wan¹, Yang Tang²

¹School of Life Sciences, Institutes of Physical Science and Information Technology, Anhui University Hefei 230601 P. R. China fanggm@ahu.edu.cn.

Chemical science

|June 28, 2024

概括

研究人员开发了一种新的Sortase介导结合和单循环 (SPLOC) 策略,以创建遗传编码的宏循环库. 这种方法有效地产生高亲和度的双循环联体,克服了药物发现传统技术的局限性.

科学领域:

生物技术是生物技术.
药用化学医学化学
分子生物学分子生物学

背景情况:

宏环在药物开发中对于向疾病蛋白质至关重要.
现有的方法,如菌体显示有局限性,包括二硫化物键不稳定性和有毒试剂.
化学宏循环化可能会损害菌体并引起副作用.

研究的目的:

开发一种新,高效和安全的方法来生成遗传编码的质宏循环库.
为了克服传统的二硫化物键形成和化学宏循环化技术的缺点.
为了发现与疾病相关的蛋白质的高亲和性联体.

主要方法:

引入了一种Sortase介导的联和单循环 (SPLOC) 策略.
利用了sortase在LPXTG识别序列的X残留物上的不自然的乱交性.
集成的低反应电友用于内循环与菌体显示的类图书馆.

主要成果:

通过使用SPLOC平台成功生成了基因编码的类宏循环库.
确定了一种高亲和度的双循环联体,向TEAD4,其解离常数 (KD) 为63.9nM.
双循环联体与其非循环对应物相比,具有102倍的结合亲和力.

结论:

该SPLOC战略为构建类宏循环提供了一个新的,有效的途径,避免有毒试剂和不稳定性问题.
这种方法代表了酶乱交的首次使用,用于生成类宏循环.
该SPLOC平台使得发现强效的疗法成为可能.

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