Mechanism of action and structural requirements of constrained peptide inhibitors of RGS proteins

Chemical Biology & Drug Design
Rebecca A RoofRichard R Neubig

Abstract

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.

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Citations

Jun 24, 2010·Molecular Pharmacology·Levi L BlazerRichard R Neubig
Jan 29, 2016·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Maciej SalagaJakub Fichna
Jul 22, 2008·Chemical Biology & Drug Design·Rebecca A RoofHenry I Mosberg
Jan 1, 2009·Progress in Molecular Biology and Translational Science·David L Roman
Sep 19, 2008·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Levi L Blazer, Richard R Neubig
Jan 14, 2010·Current Protocols in Cytometry·Levi L BlazerRichard R Neubig
Oct 23, 2019·The Journal of Biological Chemistry·Joseph B O'BrienDavid L Roman

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