Peptide inhibitors of angiotensin-I converting enzyme based on angiotensin (1–7) with selectivity for the C-terminal domain

[Display omitted] •The search for domain-specific ACE inhibitors has been the focus of this report.•Ac-Ang (2–7)-NH2 is a potential analogue to develop effective cACE inhibitors.•First dynamics simulation report of an Ang (1–7) derivative with both ACE domains.•Molecular dynamics simulations show Val3 and Tyr4 interactions with ACE subsites.•Our results can facilitate the development of domain-selective ACE inhibitors. The renin-angiotensin system (RAS) is a key regulator of human arterial pressure. Several of its effects are modulated by angiotensin II, an octapeptide originating from the action of angiotensin-I converting enzyme (ACE) on the decapeptide angiotensin-I. ACE possess two active sites (nACE and cACE) that have their own kinetic and substrate specificities. ACE inhibitors are widely used as the first-line treatment for hypertension and other heart-related diseases, but because they inactivate both ACE domains, their use is associated with serious side effects. Thus, the search for domain-specific ACE inhibitors has been the focus of intense research. Angiotensin (1–7), a peptide that also belongs to the RAS, acts as a substrate of nACE and an inhibitor of cACE. We have synthetized 15 derivatives of Ang (1–7), sequentially removing the N-terminal amino acids and modifying peptides extremities, to find molecules with improved selectivity and inhibition properties. Ac-Ang (2–7)-NH2 is a good ACE inhibitor, resistant to cleavage and with improved cACE selectivity. Molecular dynamics simulations provided a model for this peptide’s selectivity, due to Val3 and Tyr4 interactions with ACE subsites. Val3 has an important interaction with the S3 subsite, since its removal greatly reduced peptide-enzyme interactions. Taken together, our findings support ongoing studies using insights from the binding of Ac-Ang (2–7)-NH2 to develop effective cACE inhibitors.