Design and synthesis of potent myostatin inhibitory cyclic peptides
| Autor: | Akihiro Taguchi, Yoshio Hayashi, Kentaro Takayama, Akari Nakamura, Atsuhiko Taniguchi, Hiroaki Ikeyama, Cédric Rentier, Mariko Saitoh |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Clinical Biochemistry
Pharmaceutical Science Peptide Myostatin Peptides Cyclic 01 natural sciences Biochemistry Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Humans Structure–activity relationship Molecular Biology IC50 chemistry.chemical_classification Molecular Structure biology 010405 organic chemistry Circular Dichroism Organic Chemistry Skeletal muscle musculoskeletal system Amides In vitro Cyclic peptide 0104 chemical sciences 010404 medicinal & biomolecular chemistry HEK293 Cells medicine.anatomical_structure chemistry Drug Design biology.protein Lactam Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:1437-1443 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2019.02.019 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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