期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 8, 期 1, 页码 113-117出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00420
关键词
alpha-Helix; inhibitor; myostatin; peptide; structure-activity relationship
资金
- Japan Society for the Promotion of Sciences (JSPS) KAKENHI
- Platform for Drug Discovery, Informatics and Structural Life Science - Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan
- MEXT [26-8]
- [15H04658]
- Grants-in-Aid for Scientific Research [15H04658] Funding Source: KAKEN
Myostatin inhibition is one of the promising strategies for treating muscle atrophic disorders, including muscular dystrophy. It is well-known that the myostatin prodomain derived from the myostatin precursor acts as an inhibitor of mature myostatin. In our previous study, myostatin inhibitory minimum peptide 1 (WRQNTRYSRIEAIKIQILSKLRL-amide) was discovered from the mouse myostatin prodomain. In the present study, alanine scanning of 1 demonstrated that the key amino acid residues for the effective inhibitory activity are rodent specific Tyr and C-terminal aliphatic residues, in addition to N-terminal Trp residue. Subsequently, we designed five Pro-substituted peptides and examined the relationship between secondary structure and inhibitory activity. As a result, we found that Pro-substitutions of Ala or Gln residues around the center of 1 significantly decreased both alpha-helicity and inhibitory activity. These results suggested that an alpha-helical structure possessing hydrophobic faces formed around the C-terminus is important for inhibitory activity.
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