Received for publication September 14, 2007.
Revised November 12, 2007.
Accepted for publication November 13, 2007.

Small Molecule Disruption of G Protein Subunit Signaling Inhibits Neutrophil Chemotaxis and Inflammation

Abstract

G protein subunit-dependent signaling is important for chemoattractant-dependent leukocyte chemotaxis. Selective small molecule targeting of PI3-kinase catalytic activity is a target of interest for anti-inflammatory pharmaceutical development. Here we examined if small molecule inhibition of G-dependent signaling, including G-dependent activation of PI3-kinase and Rac, could inhibit chemoattractant-dependent neutrophil migration in vitro and inflammation in vivo. Small molecule G inhibitors suppressed fMLP-stimulated Rac1 activation, superoxide production, and PI3-kinase activation in differentiated HL60 cells. These compounds also blocked fMLP-dependent chemotaxis in HL60 cells and primary human neutrophils. Systemic administration inhibited paw edema and neutrophil infiltration in a mouse carrageenan-induced paw edema model. Overall the data demonstrate that targeting G-regulation may be an effective anti-inflammation strategy

Key words: Chemotactic peptides, Gi family, G protein regulation, Leukocytes/Mast cells