Development of Potent Myostatin Inhibitory Peptides through Hydrophobic Residue-Directed Structural Modification.
ACS Med Chem Lett
; 8(7): 751-756, 2017 Jul 13.
Article
en En
| MEDLINE
| ID: mdl-28740611
ABSTRACT
Myostatin, a negative regulator of skeletal muscle growth, is a promising target for treating muscle atrophic disorders. Recently, we discovered a minimal myostatin inhibitor 1 (WRQNTRYSRIEAIKIQILSKLRL-amide) derived from positions 21-43 of the mouse myostatin prodomain. We previously identified key residues (N-terminal Trp21, rodent-specific Tyr27, and all aliphatic amino acids) required for effective inhibition through structure-activity relationship (SAR) studies based on 1 and characterized a 3-fold more potent inhibitor 2 bearing a 2-naphthyloxyacetyl group at position 21. Herein, we performed 1-based SAR studies focused on all aliphatic residues and Ala32, discovering that the incorporations of Trp and Ile at positions 32 and 38, respectively, enhanced the inhibitory activity. Combining these findings with 2, a novel peptide 3d displayed an IC50 value of 0.32 µM, which is 11 times more potent than 1. The peptide 3d would have the potential to be a promising drug lead to develop better peptidomimetics.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
ACS Med Chem Lett
Año:
2017
Tipo del documento:
Article
País de afiliación:
Japón