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- 题目:
- Mechanism of action and structural requirements of constrained peptide inhibitors of RGS proteins.
- 作者:
- Roof(Rebecca A),Jin(Yafei),Roman(David L),Sunahara(Roger K),Ishii(Masaru),Mosberg(Henry I),Neubig(Richard R)
- 状态:
- 发布时间2006-04-24 , 更新时间 2013-11-21
- 期刊:
- Chem Biol Drug Des
- 摘要:
- Regulators of G-protein signaling (RGS) accelerate guanine triphosphate hydrolysis by Galpha-subunits and profoundly inhibit signaling by G protein-coupled receptors. The distinct expression patterns and pathophysiologic regulation of RGS proteins suggest that inhibitors may have therapeutic potential. We previously reported the design of a constrained peptide inhibitor of RGS4 (1: Ac-Val-Lys-[Cys-Thr-Gly-Ile-Cys]-Glu-NH2, S-S) based on the structure of the Galphai switch 1 region but its mechanism of action was not established. In the present study, we show that 1 inhibits RGS4 by mimicking and competing for binding with the switch 1 region of Galphai and that peptide 1 shows selectivity for RGS4 and RGS8 versus RGS7. Structure-activity relationships of analogs related to 1 are described that illustrate key features for RGS inhibition. Finally, we demonstrate activity of the methylene dithioether-bridged peptide inhibitor, 2, to modulate muscarinic receptor-regulated potassium currents in atrial myocytes. These data support the proposed mechanism of action of peptide RGS inhibitors, demonstrate their action in native cells, and provide a starting point for the design of RGS inhibitor drugs.
- 语言:
- eng
- DOI:
- 10.1111/j.1747-0285.2006.00373.x
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