Structure-based design, synthesis, and pharmacologic evaluation of peptide RGS4 inhibitors.
Regulators of G-protein signaling (RGS) proteins form a multifunctional signaling family. A key role of RGS proteins is binding to the G-protein Galpha-subunit and acting as GTPase-activating proteins (GAPs), thereby rapidly terminating G protein-coupled receptor (GPCR) signaling. Using the published RGS4-Gialpha1 X-ray structure we have designed and synthesized a series of cyclic peptides, modeled on the Gialpha Switch I region, that inhibit RGS4 GAP activity. These compounds should prove useful for elucidating RGS-mediated activity and serve as a starting point for the development of a novel class of therapeutic agent.
Department of Medicinal Chemistry, The University of Michigan, Ann Arbor, MI 48109, USA.
Y
Y
Jin
H
H
Zhong
J R
JR
Omnaas
R R
RR
Neubig
H I
HI
Mosberg
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D020690:GTPase-Activating Proteins / Q000378:metabolism; D020128:Inhibitory Concentration 50; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020710:RGS Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D020690:GTPase-Activating Proteins; D010456:Peptides, Cyclic; D020710:RGS Proteins; C098799:RGS4 protein