Binding Loop Substitutions in the Cyclic Peptide SFTI-1 Generate Potent and Selective Chymase Inhibitors.
J Med Chem
; 63(2): 816-826, 2020 01 23.
Article
en En
| MEDLINE
| ID: mdl-31855419
ABSTRACT
Chymase is a serine protease that is predominantly expressed by mast cells and has key roles in immune defense and the cardiovascular system. This enzyme has also emerged as a therapeutic target for cardiovascular disease due to its ability to remodel cardiac tissue and generate angiotensin II. Here, we used the nature-derived cyclic peptide sunflower trypsin inhibitor-1 (SFTI-1) as a template for designing novel chymase inhibitors. The key binding contacts of SFTI-1 were optimized by combining a peptide substrate library screen with structure-based design, which yielded several variants with potent activity. The lead variant was further modified by replacing the P1 Tyr residue with para-substituted Phe derivatives, generating new inhibitors with improved potency (Ki = 1.8 nM) and higher selectivity over closely related enzymes. Several variants were shown to block angiotensin I cleavage in vitro, highlighting their potential for further development and future evaluation as pharmaceutical leads.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
/
Péptidos Cíclicos
/
Inhibidores de Serina Proteinasa
/
Quimasas
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Australia