Medicinal Chemistry of Mid-sized Molecules on Biologically Active Peptides

Neuromedin U (NMU) displays various physiological activities including an anorexigenic effect, and the C-terminal heptapeptide-amide sequence is necessary to activate two NMU receptors (NMUR1 and NMUR2). Based on this heptapeptide, we recently developed highly active NMUR1 hexapeptide agonist 4d and NMUR2-selective hexapeptide agonist 8c. Moreover, we identified two major biodegradation sites (Phe(2)-Arg(3) and Arg(5)-Asn(6)) by the stability analysis of 4d in serum. On the other hand, myostatin is an endogenous negative regulator of skeletal muscle mass, which is recognized as a therapeutic target for muscle atrophic disorders. Recently, we successfully identified myostatin inhibitory peptides 9 and 16 (24 and 23 amino acids, respectively) with minimum sequence derived from mouse myostatin prodomain. These peptides directly bind to myostatin with K-D values of 30-36 nM. Moreover, peptide 9 significantly increased tibialis anterior muscle mass in Duchenne muscular dystrophy model mice. Therefore, these synthesized peptides would be promising mid-sized molecules for peptide-based medicinal chemistry.