Identification and mechanistic characterization of novel ACE-inhibitory peptides derived from Nattokinase

Hypertension remains a major global health challenge and is associated with increased cardiovascular risk. Angiotensin-converting enzyme (ACE) plays a pivotal role in blood pressure regulation; however, conventional synthetic ACE inhibitors are often accompanied by undesirable side effects. Nattokinase (NK), a serine protease derived from natto, has shown antihypertensive potential via bioactive peptides released during digestion. In this study, we identified two novel ACE-inhibitory peptides (LGG and TW) from simulated digestion of NK. LGG exhibited potent competitive inhibition (IC₅₀ = 10.78 μM), while TW acted noncompetitively. Molecular docking and dynamics confirmed stable interactions, and network pharmacology suggested multitarget cardiovascular regulation. These findings support the potential of NK-derived peptides as functional food components for blood pressure management.