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

The takeaway

Natural peptides that selectively block only the C-domain of ACE (not both domains) could treat blood pressure without the chronic cough and angioedema caused by current ACE inhibitors.

C-domain specificity
Targeting only ACE's C-domain could control blood pressure without the bradykinin accumulation that causes cough and angioedema

What the researchers found

The review identifies a key insight: current ACE inhibitors block both the C-domain and N-domain of ACE, which causes bradykinin to accumulate and trigger dry cough and angioedema. However, blood pressure regulation primarily involves the C-domain. Natural peptides — especially those with tryptophan at the C-terminal — could be designed or selected to inhibit only the C-domain, theoretically controlling blood pressure without the side effects.

The proposed discovery pipeline involves: isolating peptides from natural products, testing their stability against gastrointestinal enzymes (for oral delivery), selecting those with favorable amino acid compositions, and using molecular docking and dynamics to confirm C-domain-specific inhibition.

Why it matters

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.

How the study worked

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.

What this study cannot tell us

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.

How to read the evidence

This is a perspective/review article that proposes a research strategy based on established biochemistry. It does not present new experimental data, and the proposed C-domain-specific approach awaits validation.

When this study was published

Published in 2023, this is a recent perspective that reflects current understanding of ACE domain biology and natural product peptide research.

The bigger picture

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.

Questions still open

Have any natural peptides been experimentally confirmed to show C-domain-specific ACE inhibition?
Would C-domain-specific ACE inhibitory peptides achieve clinically relevant blood pressure reductions at orally achievable doses?
Could this domain-specific approach be applied to redesigning existing synthetic ACE inhibitors rather than only natural peptides?

Common questions

Why do ACE inhibitors cause a chronic dry cough?

ACE inhibitors block the enzyme that breaks down bradykinin, a peptide that causes blood vessels to dilate and stimulates cough receptors in the lungs. When bradykinin accumulates because ACE is blocked, it triggers a persistent dry cough in up to 20% of patients. This review proposes that blocking only one part of ACE (the C-domain) could control blood pressure without this bradykinin buildup.

Can food-derived peptides actually lower blood pressure?

Many peptides from foods like milk, fish, and soybeans have been shown to inhibit ACE in laboratory tests, and some have shown modest blood pressure-lowering effects in clinical trials. The challenge is that these peptides need to survive digestion, be absorbed into the bloodstream, and reach ACE at high enough concentrations to be effective. This review argues the field needs to focus on domain-specific inhibition to make food-derived peptides clinically meaningful.

Read the original research

Is It Still Relevant to Discover New ACE Inhibitors from Natural Products? YES, but Only with Comprehensive Approaches to Address the Patients' Real Problems: Chronic Dry Cough and Angioedema.

Molecules (Basel, Switzerland), 28(11)

View on PubMed ↗Publisher’s paper ↗

Citation

Manoharan, Sivananthan. (2023). Is It Still Relevant to Discover New ACE Inhibitors from Natural Products? YES, but Only with Comprehensive Approaches to Address the Patients' Real Problems: Chronic Dry Cough and Angioedema.. Molecules (Basel, Switzerland), 28(11). https://doi.org/10.3390/molecules28114532