Plasma Kallikrein Inhibitors for Multiple Disorders: Current Advances and Perspectives

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.