Design, Synthesis, and Characterization of a Single-Chain Peptide Antagonist for the Relaxin-3 Receptor RXFP3

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• 作者：Linda M. Haugaard-Kedstr枚m ; Fazel Shabanpoor ; Mohammed Akhter Hossain ; Richard J. Clark ; Philip J. Ryan ; David J. Craik ; Andrew L. Gundlach ; John D. Wade ; Ross A. D. Bathgate ; K. Johan Rosengren
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：April 6, 2011
• 年：2011
• 卷：133
• 期：13
• 页码：4965-4974
• 全文大小：1122K
• 年卷期：v.133,no.13(April 6, 2011)
• ISSN：1520-5126

文摘

Relaxin-3 is a two-chain disulfide-rich peptide that is the ancestral member of the relaxin peptide family and, together with its G protein-coupled receptor RXFP3, is highly expressed in the brain. Strong evolutionary conservation of relaxin-3 suggests a critical biological function and recent studies have demonstrated modulation of sensory, neuroendocrine, metabolic, and cognitive systems. However, detailed studies of central relaxin-3-RXFP3 signaling have until now been severely hampered by the lack of a readily available high-affinity antagonist for RXFP3. Previous studies have utilized a complex two-chain chimeric relaxin peptide, R3(B螖23鈭?7)R/I5, in which a truncated relaxin-3 B-chain carrying an additional C-terminal Arg residue was combined with the insulin-like peptide 5 (INSL5) A-chain. In this study we demonstrate that, by replacing the native Cys in this truncated relaxin-3 B-chain with Ser, a single-chain linear peptide of 23 amino acids that retains high-affinity antagonism for RXFP3 can be achieved. In vivo studies demonstrate that this peptide, R3 B1鈭?2R, antagonized relaxin-3/RXFP3 induced increases in feeding in rats after intracerebroventricular injection. Thus, R3 B1鈭?2R represents an excellent tool for biological studies probing relaxin pharmacology and a lead molecule for the development of synthetically tractable, single-chain RXFP3 modulators for clinical use.