Medicinal chemistry focused on mid-sized peptides derived from biomolecules

Abstract

Biomolecule-derived peptides are attractive research resources to develop drugs and elucidate the basic mechanisms of life phenomena. This review article focuses on two biomolecules called "neuromedin U (NMU)" and "myostatin" that are deeply involved in obesity and muscle weakness caused by modern lifestyles and aging. A structure-activity relationship (SAR) study based on a biomolecule reveals the structural features required for the biological activity and gives clues leading the drug discovery process. NMU activates two types of receptors (NMUR1 and NMUR2). NMU, which is an attractive candidate for treating obesity, displays a variety of physiological actions in addition to appetite suppression. The discovery of useful receptor-selective agonists helps in elucidating the detailed roles of the respective receptors for each action and in developing therapeutic drugs based on receptor function. Hence, SAR studies focused on the amidated C-terminal heptapeptide of NMU were carried out to obtain selective agonists. Consequently, the respective hexapeptidic NMUR1 and NMUR2 agonists CPN-267 and CPN-116 were discovered. Myostatin, an endogenous negative regulator of skeletal muscle mass, is a promising target for treating muscle atrophy disorders. Focused on the inactivation mechanism of mature myostatin by the myostatin precursor-derived prodomain, a core peptide (23-mer) for effective myostatin inhibition was identified from the mouse myostatin prodomain sequence. The SAR study based on this core peptide afforded a 25-fold more potent derivative (16-mer), which increased skeletal muscle mass and hindlimb grip strength. Therefore, this derivative could be a novel platform for a peptidic drug useful in the treatment of muscle atrophy.