《生命科学》 2024, 36(7): 951-961

重组蛋白药物长效化策略

夏玲慧 , 龙睿灵 , 赛乃外尔古丽·吾斯曼 , 丁　明^*

中国药科大学生命科学与技术学院，南京 210009

摘　要：

与传统小分子药物相比，重组蛋白药物具有高活性、高亲和性、低毒性等显著优势，但蛋白酶降解、肾脏清除、肝脏代谢和免疫清除等因素造成的短血浆半衰期，严重限制了其临床应用，因此发展相应的长效化策略尤为重要。其中，构建突变体、环化和钉合肽等结构修饰策略，可增加药物结构稳定性，屏蔽蛋白酶识别位点；以聚乙二醇修饰为代表的化学聚合物修饰，可增加药物流体动力学体积；以Fc 融合为代表的天然蛋白融合策略，可通过相应受体介导的机制减少肝脏代谢。本文将结合实例，对一些经典的蛋白药物长效化策略如结构修饰、化学聚合物修饰、天然蛋白融合等进行总结与讨论。

通讯作者：丁　明 , Email:mingding@cpu.edu.cn

Half-life extension strategies for recombinant protein drugs

XIA Ling-Hui , LONG Rui-Ling , WUSIMAN Sainaiwaierguli , DING Ming^*

School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China

Abstract:

Compared with traditional small molecule drugs, recombinant protein drugs have significant advantages, such as higher activity and affinity, and lower toxicity. However, the short plasma half-life caused by factors such as protease degradation, renal elimination, liver metabolism and immune clearance severely limits clinical application of recombinant protein drugs. Therefore, developing corresponding half-life extension strategies is particularly important. Structural modification strategies such as mutants, cyclization, and stapled peptide can increase structural stability of drugs and shield protease recognition sites. Chemical polymer modification represented by polyethylene glycol modification can increase the volume of fluid dynamics of drugs. The natural protein fusion strategy represented by Fc fusion can reduce liver metabolism through corresponding receptor mediated mechanisms. In this paper, we summarize and discuss some classic half-life extension strategies for recombinant protein drugs combined with specific applications, such as structural modification, chemical polymer modification and natural protein fusion.

Communication Author：DING Ming , Email:mingding@cpu.edu.cn