Development of Potent Myostatin Inhibitory Peptides through Hydrophobic Residue-Directed Structural Modification.

Myostatin, a negative regulator of skeletal muscle growth, is a promising target for treating muscle atrophic disorders. Recently, we discovered a minimal myostatin inhibitor (WRQNTRYSRIEAIKIQILSKLRL-amide) derived from positions 21-43 of the mouse myostatin prodomain. We previously identified key residues (N-terminal Trp, rodent-specific Tyr, and all aliphatic amino acids) required for effective inhibition through structure-activity relationship (SAR) studies based on and characterized a 3-fold more potent inhibitor bearing a 2-naphthyloxyacetyl group at position 21. Herein, we performed -based SAR studies focused on all aliphatic residues and Ala, discovering that the incorporations of Trp and Ile at positions 32 and 38, respectively, enhanced the inhibitory activity. Combining these findings with , a novel peptide displayed an IC value of 0.32 μM, which is 11 times more potent than . The peptide would have the potential to be a promising drug lead to develop better peptidomimetics.