| Texto completo | |
| Autor(es): |
Silva, Rogerio L. da
;
Papakyriakou, Athanasios
;
Carmona, Adriana K.
;
Spyroulias, Georgios A.
;
Sturrock, Edward D.
;
Bersanetti, Patricia A.
;
Nakaie, Clovis R.
Número total de Autores: 7
|
| Tipo de documento: | Artigo Científico |
| Fonte: | BIOORGANIC CHEMISTRY; v. 129, p. 11-pg., 2022-10-25. |
| Resumo | |
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) | |
| Processo FAPESP: | 18/23269-9 - Estudos sintéticos e estruturais de peptídeos e polímeros: do aprimoramento da metodologia de síntese e da procura de derivados peptídicos para aplicações biotecnológicas |
| Beneficiário: | clovis ryuichi nakaie |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |