Biasing G protein coupled receptor signaling using pepducins
G protein coupled receptor (GPCR) drug discovery has traditionally focused on the orthosteric ligand binding site as the primary target for drug development. Although it is estimated that approximately 50% of FDA approved pharmaceuticals target an aspect of GPCR signaling, conventional methods of drug design may be limiting the pharmacological profiles that can be elicited. As GPCRs are now appreciated to couple to multiple intracellular signaling pathways, the ability to selectively promote or inhibit the activation of these pathways could be invaluable. In the field of GPCRs, this notion is called biased signaling or functional selectivity. To date, there are very few orthosteric biased agonists compared to the rich diversity in pharmacology that biased signaling has the potential to offer. With this in mind, our efforts forgo the ligand binding pocket and target the intracellular surface of a GPCR using pepducins. Pepducins are lipidated peptides derived from the intracellular loops of a given GPCR. Pepducins operate as agonists or antagonists of GPCR signaling and have demonstrated the ability to promote biased signaling profiles. This thesis provides the functional and mechanistic characterization of 3 unique pepducins along with their implication in the treatment of human disease. In manuscript I, we report a first-in-class Gs-biased pepducin agonist of the β2-adrenergic receptor that may serve as a template for next-generation asthma pharmaceuticals. In manuscript II, we described the promiscuous activity of P4pal-10 and investigate the therapeutic potential of broad-based Gq inhibition in the airway by receptor-dependent and receptor-independent mechanisms. In manuscript III, a potent β-arrestin-biased pepducin of the β2-adrenergic receptor is used to detail the relative contribution of β-arrestin-biased signaling in the treatment of congestive heart failure.
Carr, Richard, "Biasing G protein coupled receptor signaling using pepducins" (2015). ETD Collection for Thomas Jefferson University. AAI3728521.