title: Effect of N-Terminal Acylation on the Activity of Myostatin Inhibitory Peptides.
abstract: Inhibition of myostatin, which negatively regulates skeletal muscle growth, is a promising strategy for the treatment of muscle atrophic disorders, such as muscular dystrophy, cachexia and sarcopenia. Recently, we identified peptide A (H-WRQNTRYSRIEAIKIQILSKLRL-NH2 ), the 23-amino-acid minimum myostatin inhibitory peptide derived from mouse myostatin prodomain, and highlighted the importance of its N-terminal tryptophan residue for the effective inhibition. In this study, we synthesized a series of acylated peptide derivatives focused on the tryptophan residue to develop potent myostatin inhibitors. As a result of the investigation, a more potent derivative of peptide A was successfully identified in which the N-terminal tryptophan residue is replaced with a 2-naphthyloxyacetyl moiety to give an inhibitory peptide three times (1.19±0.11 μm) more potent than parent peptide A (3.53±0.25 μm). This peptide could prove useful as a new starting point for the development of improved inhibitory peptides.
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takayama
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Akari
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Cédric
authors.initials: C
authors.lastname: Rentier
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Mino
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Tomo
authors.initials: T
authors.lastname: Asari
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Saga
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Fumika
authors.initials: F
authors.lastname: Yakushiji
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan. yhayashi@toyaku.ac.jp.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000215:Acylation; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D055435:Myostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C525911:MSTN protein, human; D055435:Myostatin; D010455:Peptides
keywords: TGF-β superfamily; acylation; inhibitors; muscle atrophic disorders; myostatin