G-protein-directed ligand discovery with peptide combinatorial libraries

Modulators of G-protein signaling have a central role in controlling cell physiology and represent over half of all marketed prescription drugs. G-protein pathways have traditionally been targeted by developing ligands to the extracellular surface of a small subset of the estimated similar to 1000 G-protein-coupled receptors in humans. The intracellular machinery, consisting of the cytosolic receptor surfaces and heterotrimeric G proteins, provides an equivalent diversity of targets that has remained relatively unexplored until now. This review summarizes recent efforts using combinatorial peptide libraries to develop new G-protein signaling modulators targeting intracellular components.