Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 27, Issue 7, Pages 1437-1443Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.02.019
Keywords
Myostatin; Inhibitor; Peptide; Cyclization; Structure-activity relationship
Funding
- Japan Society for the Promotion of Sciences (JSPS) KAKENHI [15H04658, 16F16413]
- MEXT-supported Program for the Strategic Research Foundation at Private Universities
- Intramural Research Grant for Neurological and Psychiatric Disorders on NCNP [29-4]
- Grants-in-Aid for Scientific Research [15H04658, 16F16413] Funding Source: KAKEN
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Myostatin is a negative regulator of skeletal muscle growth and myostatin inhibitors are promising lead compounds against muscle atrophic disorders such as muscular dystrophy. Previously, we published the first report of synthetic myostatin inhibitory 23-mer peptide 1, which was identified from a myostatin precursor-derived prodomain protein. Our structure-activity relationship study afforded the potent inhibitory peptide 3. In this paper, we report an investigation of the synthesis of conformationally-constrained cyclic peptide based on the linear peptide 3. To examine the potency of side chain-to-side chain cyclized peptides, a series of disulfide-, lactam-and diester-bridged derivatives were designed and synthesized, and their myostatin inhibitory activities were evaluated. The diester-bridged peptide (11) displayed potent inhibitory activity with an in vitro IC50 value of 0.26 mu M, suggesting that it could serve as a new platform for development of cyclic peptide inhibitors.
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