Intracellular inhibitors of GPCRs

Receptors coupled with G proteins (GPCRs) control numerous cellular functions, but the intracellular interaction between receptors and G proteins has proved difficult to block specifically. In September 23 Nature Medicine, Lidija Covic and colleagues at Tufts University School of Medicine, Boston, US, show that pepducins enter cells and inhibit signal transference from membrane receptors to G proteins (Nature Medicine, DOI:10.1038/nm760, September 23, 2002).

Using platelets Covic et al. observed that attachment of a palmitate lipid to peptides based on the third intracellular loop of protease-activated receptor 1 or 4 (PAR1, PAR4) yielded potent inhibitors of thrombin-mediated aggregation. In addition, they showed that infusion of the anti-PAR4 pepducin into mice extended bleeding time and protected against systemic platelet activation.

"The deployment of i3-loop pepducins provides a simple and powerful approach to determine the effect of pharmacological disruption of GPCRs that lack a known extracellular antagonist," conclude the authors.