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

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 <b>1</b> (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 <b>1</b> and characterized a 3-fold more potent inhibitor <b>2</b> bearing a 2-naphthyloxyacetyl group at position 21. Herein, we performed <b>1</b>-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 <b>2</b>, a novel peptide <b>3d</b> displayed an IC₅₀ value of 0.32 μM, which is 11 times more potent than <b>1</b>. The peptide <b>3d</b> would have the potential to be a promising drug lead to develop better peptidomimetics.