Introduction: Serine proteases play pivotal roles in physiological and pathological processes, including cancer, cardiovascular dysfunction, inflammation, and neurodegeneration. Methods: This review systematically explores therapeutic strategies targeting serine proteases, emphasizing mechanisms of inhibition, clinical relevance, and recent advancements in inhibitor design. Results: Inhibitors include small molecules (dabigatran, which displays strong inhibitory effects, although its binding affinity depends on the peptide chain length), peptides (macrocyclic compounds), antibodies, and protein therapeutics such as native serine protease inhibitors (serpins), including antithrombin, α1-antitrypsin, and C1-inhibitor, which play critical regulatory and therapeutic roles. These agents utilize covalent and non-covalent mechanisms, transitionstate mimicry, and steric or allosteric inhibition. Clinical data support their efficacy, but limitations include off-target effects, pharmacokinetic instability, and resistance (e.g., HCV protease mutations). Discussion: Emerging solutions involve targeting novel proteases like furin and mesotrypsin, dual-action inhibitors that engage both serine and metallo-carbapenemases, and delivery via nanotechnology. PROTACs and activity-based probes enhance target validation and drug design. Conclusion: Serine protease inhibitors offer promising therapeutic benefits across diseases. Advancements in selectivity, delivery, and resistance management will drive future clinical applications.
Bharti et al. (Fri,) studied this question.