Haonan Liu, Yujun Deng, Jiali Liu, Zhiwei Wang, Xueqin Hu, Yajun Duan, Yuanli Chen, Zhouling Xie
Plasma kallikrein (PKal) is a pivotal serine protease involved in the regulation of the kallikrein-kinin system, the complement system, and several other biological pathways. Inhibition of PKal has become a key therapeutic strategy for hereditary angioedema, with four PKal-targeting agents approved by the U.S. FDA. The therapeutic potential of PKal inhibition is also being actively explored in other conditions, such as diabetic macular edema and COVID-19, through ongoing clinical trials. Here, we provide a comprehensive analysis of the biological functions of PKal across diverse signaling pathways, PKal-associated diseases, and recent clinical advancements of PKal-targeting agents. Furthermore, we spotlight the optimization strategies and key structure-activity relationships underlying the discovery and development of small-molecule PKal inhibitors, offering insights that may inform future PKal drug development for hereditary angioedema and other PKal-related diseases.