Research Article: Mechanism of Action and Structural Requirements of Constrained Peptide Inhibitors of RGS Proteins

• Published in: Chemical biology & drug design 2006-04, Vol.67 (4), p.266-274
• Main Authors: Roof, Rebecca A, Jin, Yafei, Roman, David L, Sunahara, Roger K, Ishii, Masaru, Mosberg, Henry I, Neubig, Richard R
• Format: Article
• Language: English
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/j.1747-0285.2006.00373.x

Regulators of G-protein signaling (RGS) accelerate guanine triphosphate hydrolysis by G alpha -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-NH sub(2), S-S) based on the structure of the G alpha i 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 G alpha i 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.