Development of Myostatin Inhibitory <scp>d</scp>-Peptides to Enhance the Potency, Increasing Skeletal Muscle Mass in Mice

Abstract

Myostatin is a key negative regulator of skeletal muscle growth, and myostatin inhibitors are attractive tools for the treatment of muscular atrophy. Previously, we reported a series of 14-29-mer peptide myostatin inhibitors, including a potent derivative, MIPE-1686, a 16-mer N-terminal-free l-peptide with three unnatural amino acids and a propensity to form β-sheets. However, the <i>in vivo</i> biological stability of MIPE-1686 is a concern for its development as a drug. In the present study, to develop a more stable myostatin inhibitory d-peptide (MID), we synthesized various <i>retro-inverso</i> versions of a 16-mer peptide. Among these, an arginine-containing derivative, MID-35, shows a potent and equivalent <i>in vitro</i> myostatin inhibitory activity equivalent to that of MIPE-1686 and considerable stability against biodegradation. The <i>in vivo</i> potency of MID-35 to increase the tibialis anterior muscle mass in mice is significantly enhanced over that of MIPE-1686, and MID-35 can serve as a new entity for the prolonged inactivation of myostatin in skeletal muscle.