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 µM, suggesting that it could serve as a new platform for development of cyclic peptide inhibitors.
Keywords: Cyclization; Inhibitor; Myostatin; Peptide; Structure-activity relationship.
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