Why We Still Need New ACE Inhibitor Peptides from Natural Sources — And How to Find Better Ones

This is a review/perspective article that synthesizes current knowledge about ACE enzyme structure, the mechanism of ACE inhibitor side effects, and the potential of natural product-derived peptides. The author proposes a computational and experimental framework for discovering domain-specific ACE inhibitory peptides, incorporating molecular docking, dynamics simulations, and gastrointestinal stability testing.

ACE inhibitors are among the most prescribed cardiovascular medications worldwide, and recent evidence suggests they may be preferable to ARBs (the alternative) for certain patient populations, including those with both hypertension and diabetes. But the cough and angioedema side effects drive many patients to switch medications. If domain-specific ACE inhibitory peptides from food sources could be developed, they could provide blood pressure control without these side effects — potentially as functional foods or as pharmaceutical candidates.

Food-derived bioactive peptides with ACE inhibitory activity have been extensively studied, with hundreds identified from milk, fish, soy, and other sources. However, most research has focused on total ACE inhibition without considering domain specificity. This review reframes the field by arguing that domain-specific inhibition is the key to clinical relevance. It connects peptide chemistry, structural biology, and clinical pharmacology in a way that could guide more purposeful bioactive peptide discovery.

This is a perspective article that proposes a strategy but does not present experimental validation. The assumption that C-domain-specific peptide inhibitors would avoid bradykinin accumulation, while mechanistically reasonable, has not been clinically demonstrated. Natural peptides may face challenges with bioavailability, stability, and potency compared to established pharmaceutical ACE inhibitors. The practical feasibility of the proposed discovery pipeline is not demonstrated.