Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Peptide Tool-Driven Functional Elucidation of Biomolecules Related to Endocrine System and Metabolism
Kentaro Takayama
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2022 Volume 70 Issue 6 Pages 413-419


The enhancement of basic research based on biomolecule-derived peptides has the potential to elucidate their biological function and lead to the development of new drugs. In this review, two biomolecules, namely “neuromedin U (NMU)” and “myostatin,” are discussed. NMU, a neuropeptide first isolated from the porcine spinal cord, non-selectively activates two types of receptors (NMUR1 and NMUR2) and displays a variety of physiological actions, including appetite suppression. The development of receptor-selective regulators helps elucidate each receptor’s detailed biological roles. A structure–activity relationship (SAR) study was conducted to achieve this purpose using the amidated C-terminal core structure of NMU for receptor activation. Through obtaining receptor-selective hexapeptide agonists, molecular functions of the core structure were clarified. Myostatin is a negative regulator of skeletal muscle growth and has attracted attention as a target for treating atrophic muscle disorders. Although the protein inhibitors, such as antibodies and receptor-decoys have been developed, the inhibition by smaller molecules, including peptides, is less advanced. Focusing on the inactivation mechanism by prodomain proteins derived from myostatin-precursor, a first mid-sized α-helical myostatin-inhibitory peptide (23-mer) was identified from the mouse sequence. The detailed SAR study based on this peptide afforded the structural requirements for effective inhibition. The subsequent computer simulation proposed the docking mode at the activin type I receptor binding site of myostatin. The resulting development of potent inhibitors suggested the existence of a more appropriate binding mode linked to their β-sheet forming properties, suggesting that further investigations might be needed.

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