Development of Myostatin Inhibitory D-Peptides to Enhance the Potency, Increasing Skeletal Muscle Mass in Mice

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 beta-sheets. However, the in vivo 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 retro-inverso versions of a 16-mer peptide. Among these, an arginine-containing derivative, MID-35, shows a potent and equivalent in vitro myostatin inhibitory activity equivalent to that of MIPE-1686 and considerable stability against biodegradation. The in vivo 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.

Automated summary

A new myostatin inhibitory peptide, MID-35, has been developed with improved stability and resistance to biodegradation. It significantly increases the tibialis anterior muscle mass in mice and can be used for prolonged inactivation of myostatin in skeletal muscle.