Structural and Functional Characterization of Serine Proteases in Inflammatory Pathways: Implications for Targeted Therapeutics

Background: Serine proteases constitute a large family of enzymes that play essential roles in coagulation, complement activation, tissue remodeling, and immune responses. Increasingly, they have been implicated as critical mediators of inflammation, linking proteolytic activity to the initiation and propagation of both acute and chronic inflammatory diseases. Despite their functional importance, the structural basis for substrate specificity, regulatory mechanisms, and therapeutic modulation of serine proteases in inflammatory contexts remains incompletely understood. Methods and Results: This review integrates structural biology, enzymology, and immunology data to provide a comprehensive overview of key serine proteases involved in inflammatory signaling, including neutrophil elastase, proteinase 3, cathepsin G, granzyme B, and kallikreins. High-resolution crystallographic studies have elucidated active site conformations, exosites, and allosteric domains that determine substrate selectivity and protease regulation. Functional assays and in vivo models have demonstrated that dysregulated serine protease activity contributes to endothelial dysfunction, leukocyte infiltration, extracellular matrix degradation, and cytokine activation in conditions such as sepsis, rheumatoid arthritis, asthma, and inflammatory bowel disease. Protease inhibitors—ranging from synthetic small molecules and engineered serpins to monoclonal antibodies and RNA-based therapeutics—are under active development, with several candidates showing promise in preclinical or early-phase clinical trials. Notably, selective targeting of pathogenic proteolytic cascades without impairing host defense remains a key challenge. Advances in protease-specific imaging and biomarker discovery are further enabling personalized approaches to inflammation resolution. Conclusion: Structural and functional insights into serine proteases have illuminated their central role in inflammation and opened new avenues for the development of targeted anti-inflammatory therapies.