西湖大学党波波课题组研究出速效共价蛋白药物的高通量选择系统。相关论文于2026年4月2日发表于国际顶尖学术期刊《科学》杂志上。

研究组开发了一个酵母展示平台，结合化学选择性修饰，可以选择快速作用的共价蛋白，而不会增加战斗部的内在反应性。利用该系统，该研究团队设计了一个共价的程序性死亡配体1（PD-L1）拮抗纳米体，具有快速交联动力学(k_obs = 0.18 min^-1, t_1/2 = 3.8 min)，与恩伐利单抗和阿特唑单抗相比，肿瘤抑制得到改善。同样，该课题组人员设计了一种速效共价白介素-18 (IL-18) (k_obs = 0.54 min^-1, t_1/2 = 1.3min)和一个靶向SARS-CoV-2受体结合域（RBD）的共价微小蛋白，证明了跨蛋白质模式的适用性。

据了解，共价蛋白药物具有治疗潜力，但受到缓慢的靶标结合和缺乏高通量选择平台的限制。快速的共价结合需要对亲和力、稳定性和战斗部几何形状进行协调优化，这是一个本质上多维的挑战。

附：英文原文

Title: A high-throughput selection system for fast-acting covalent protein drugs

Author: Qiongxuan Fan, Jiahao Mei, Tian Li, Chuanlong Zang, Mengjiao Li, Jing Tang, You Xu, Ge Yu, Dandan Liu, Kai Chen, Bing Yang, Jing Huang, Ting Zhou, Bobo Dang

Issue&Volume: 2026-04-02

Abstract: 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—an intrinsically multidimensional challenge. We develop a yeast display platform coupled with chemoselective modification that enables selection of fast-acting covalent proteins without increasing intrinsic warhead reactivity. Using this system, we engineered a covalent programmed death-ligand 1 (PD-L1) antagonistic nanobody with rapid crosslinking kinetics (kobs = 0.18 min1, t1/2 = 3.8 min) and improved tumor suppression compared with envafolimab and atezolizumab. Similarly, we engineered a fast-acting covalent interleukin-18 (IL-18) (kobs = 0.54 min1, t1/2 = 1.3 min) and a covalent miniprotein targeting the receptor binding domain (RBD) of SARS-CoV-2, demonstrating applicability across protein modalities.

DOI: adv3081

Source: https://www.science.org/doi/10.1126/science.adv3081