Development of a Single-Chain Peptide Agonist of the Relaxin-3 Receptor Using Hydrocarbon Stapling
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- Julien Tailhades
- Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3052, Australia
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- Mohammed Akhter Hossain
- Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3052, Australia
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- Fazel Shabanpoor
- Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3052, Australia
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- Keiko Hojo
- Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan
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- Hanna E. Kastman
- Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3052, Australia
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- Emma E. K. Ong-Pålsson
- Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3052, Australia
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- Lilian L. L. Wong
- Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3052, Australia
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- Andrew L. Gundlach
- Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3052, Australia
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- Sherie Ma
- Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3052, Australia
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- K. Johan Rosengren
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
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- John D. Wade
- Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3052, Australia
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- Ross A. D. Bathgate
- Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3052, Australia
書誌事項
- 公開日
- 2016-08-08
- 資源種別
- journal article
- DOI
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- 10.1021/acs.jmedchem.6b00265
- 公開者
- American Chemical Society (ACS)
この論文をさがす
説明
Structure-activity studies of the insulin superfamily member, relaxin-3, have shown that its G protein-coupled receptor (RXFP3) binding site is contained within its central B-chain α-helix and this helical structure is essential for receptor activation. We sought to develop a single B-chain mimetic that retained agonist activity. This was achieved by use of solid phase peptide synthesis together with on-resin ruthenium-catalyzed ring closure metathesis of a pair of judiciously placed i,i+4 α-methyl, α-alkenyl amino acids. The resulting hydrocarbon stapled peptide was shown by solution NMR spectroscopy to mimic the native helical conformation of relaxin-3 and to possess potent RXFP3 receptor binding and activation. Alternative stapling procedures were unsuccessful, highlighting the critical need to carefully consider both the peptide sequence and stapling methodology for optimal outcomes. Our result is the first successful minimization of an insulin-like peptide to a single-chain α-helical peptide agonist which will facilitate study of the function of relaxin-3.
収録刊行物
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- Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry 59 (16), 7445-7456, 2016-08-08
American Chemical Society (ACS)
