快速共价蛋白药物的高通量筛选系统

Qiongxuan Fan1,2,3,4†, Jiahao Mei1,2,3,4†, Tian Li2,3,4*†, Chuanlong Zang2,3,4†, Mengjiao Li2,3,4†, Jing Tang3,5†, You Xu2,3,4, Ge Yu2,3,4, Dandan Liu6, Kai Chen2,3,4, Bing Yang6, Jing Huang2,3,4, Ting Zhou3,5*, Bobo Dang2,3,4* Covalent protein drugs offer therapeutic potential but are limited by slow target engagement and the absence of high-throughput selection platforms. Rapid covalent binding requires coordinated optimization of affinity, stability, and warhead geometry, which is an intrinsically multidimensional challenge. We developed a yeast display platform coupled with chemoselective modification that enables selection of fast-acting covalent proteins without increasing intrinsic warhead reactivity. …