A modified version of the natural peptide angiotensin (1-7) selectively inhibits one of ACE's two active sites, potentially enabling blood pressure drugs with fewer side effects.
Selective cACE inhibitionAc-Ang (2-7)-NH2 selectively blocks the C-terminal ACE domain while sparing the N-terminal domain, unlike current non-selective ACE inhibitors
What the researchers found
Among 15 synthesized derivatives of angiotensin (1-7), Ac-Ang (2-7)-NH2 emerged as the most promising: it is a good ACE inhibitor, resistant to enzymatic cleavage, and shows improved selectivity for the C-terminal domain (cACE) over the N-terminal domain (nACE). Molecular dynamics simulations identified key interactions — Val3 and Tyr4 with ACE subsites, particularly Val3's interaction with the S3 subsite — as critical for the peptide's selectivity. Removing Val3 greatly reduced peptide-enzyme interactions.
Why it matters
ACE inhibitors are among the most prescribed drugs worldwide for hypertension and heart disease, but side effects from non-selective inhibition (particularly chronic cough) affect up to 15% of users. Domain-selective ACE inhibitors could maintain blood pressure control while reducing these side effects, improving quality of life for millions of patients.
How the study worked
Fifteen peptide derivatives of angiotensin (1-7) were synthesized by systematically removing N-terminal amino acids and modifying peptide ends. Each was tested for ACE inhibition potency and domain selectivity (nACE vs cACE). Resistance to enzymatic cleavage was assessed. Molecular dynamics simulations modeled peptide-enzyme binding to explain selectivity at the molecular level.
What this study cannot tell us
This is entirely an in vitro and computational study. No animal or human testing was performed. The actual blood pressure-lowering effect and safety of Ac-Ang (2-7)-NH2 in living organisms is unknown. Peptide drugs face significant oral bioavailability challenges that were not addressed. The degree of selectivity improvement was not quantified with specific fold-change values in the abstract.
How to read the evidence
This is an early-stage drug discovery study combining peptide synthesis, in vitro enzyme assays, and computational modeling. While the approach is scientifically sound, it represents the earliest phase of drug development with no in vivo validation.
When this study was published
Published in 2022, this study contributes to the ongoing effort to develop domain-selective ACE inhibitors, a goal that has been pursued for over two decades.
The bigger picture
The renin-angiotensin system is one of the most important drug targets in cardiovascular medicine. Moving from non-selective to domain-selective ACE inhibition represents a precision medicine approach to blood pressure control. This work demonstrates that natural peptide hormones can serve as templates for designing improved therapeutics — a concept applicable across peptide pharmacology.
Questions still open
- Would Ac-Ang (2-7)-NH2 or its derivatives effectively lower blood pressure in animal models while producing fewer side effects than current ACE inhibitors?
- Can the selectivity insights from molecular dynamics be used to design non-peptide small molecules with similar cACE selectivity?
- How does the cACE selectivity of this peptide compare to other domain-selective ACE inhibitors in development?
Common questions
Why does blocking both ACE sites cause side effects?
What is angiotensin (1-7) and why use it as a starting point?
Read the original research
Peptide inhibitors of angiotensin-I converting enzyme based on angiotensin (1-7) with selectivity for the C-terminal domain.
Bioorganic chemistry, 129, 106204
Citation
da Silva, Rogerio L; Papakyriakou, Athanasios; Carmona, Adriana K; Spyroulias, Georgios A; Sturrock, Edward D; Bersanetti, Patrícia A; Nakaie, Clovis R. (2022). Peptide inhibitors of angiotensin-I converting enzyme based on angiotensin (1-7) with selectivity for the C-terminal domain.. Bioorganic chemistry, 129, 106204. https://doi.org/10.1016/j.bioorg.2022.106204