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

Rebecca A Roof; Yafei Jin; David L Roman; Roger K Sunahara; Masaru Ishii; Henry I Mosberg; Richard R Neubig

doi:10.1111/j.1747-0285.2006.00373.x

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

Journal article

Open access

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

Rebecca A Roof, Yafei Jin, David L Roman, Roger K Sunahara, Masaru Ishii, Henry I Mosberg and Richard R Neubig

Chemical biology & drug design, Vol.67(4), pp.266-274

04/2006

DOI: 10.1111/j.1747-0285.2006.00373.x

PMID: 16629824

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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.

Glycine - metabolism

Humans

Rats, Inbred WKY

Male

Peptides, Cyclic - pharmacology

Acetylcholine - metabolism

Structure-Activity Relationship

GTPase-Activating Proteins - metabolism

Peptides, Cyclic - chemistry

Peptides, Cyclic - metabolism

Time Factors

G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism

RGS Proteins - metabolism

RGS Proteins - antagonists & inhibitors

Glycine - genetics

GTP-Binding Protein alpha Subunits - metabolism

Acetylcholine - pharmacology

Peptides, Cyclic - physiology

Rats

Serine - genetics

GTP-Binding Protein alpha Subunits - genetics

Serine - metabolism

Patch-Clamp Techniques

Animals

GTP Phosphohydrolases - metabolism

Myocytes, Cardiac - drug effects

Myocytes, Cardiac - physiology

Kinetics

Details

Title: Subtitle: Mechanism of action and structural requirements of constrained peptide inhibitors of RGS proteins
Creators: Rebecca A Roof - Department of Pharmacology, 1150 W. Medical Center Dr, University of Michigan, Ann Arbor, MI 48109, USA
Yafei Jin
David L Roman
Roger K Sunahara
Masaru Ishii
Henry I Mosberg
Richard R Neubig
Resource Type: Journal article
Publication Details: Chemical biology & drug design, Vol.67(4), pp.266-274
DOI: 10.1111/j.1747-0285.2006.00373.x
PMID: 16629824
NLM abbreviation: Chem Biol Drug Des
ISSN: 1747-0277
eISSN: 1747-0285
Publisher: England
Grant note: DA03910 / NIDA NIH HHS T32 GM008597 / NIGMS NIH HHS GM39561 / NIGMS NIH HHS
Language: English
Date published: 04/2006
Academic Unit: Pharmacy; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984070979002771

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