| Full text | |
| Author(s): |
Silva, Rogerio L. da
;
Papakyriakou, Athanasios
;
Carmona, Adriana K.
;
Spyroulias, Georgios A.
;
Sturrock, Edward D.
;
Bersanetti, Patricia A.
;
Nakaie, Clovis R.
Total Authors: 7
|
| Document type: | Journal article |
| Source: | BIOORGANIC CHEMISTRY; v. 129, p. 11-pg., 2022-10-25. |
| Abstract | |
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. (AU) | |
| FAPESP's process: | 18/23269-9 - Synthetic and structural studies of peptide and polymers: from the improvement of the synthesis methodology and the search for peptide derivatives for biotechnological applications |
| Grantee: | Clovis Ryuichi Nakaie |
| Support Opportunities: | Regular Research Grants |