Discovering the next generation of GPCR-targeted therapeutics

As the field has learned more and more about how GPCRs signal, the desired properties in drug leads have changed along the way. While receptor specificity is still important, different drugs that activate the same receptor can signal through totally distinct intracellular pathways (e.g. ß-arrestin vs. G-protein signaling bias) and thus have distinct responses in vivo. In addition to conventional “orthosteric” GPCR ligands, allosteric modulators can bind to GPCRs in different sites on the protein and enhance or depress tightly regulated endogenous signaling pathways. We will develop and deploy new screening approaches to leverage the complexity intrinsic to GPCR signaling. Selective activation of GPCR (or multiple GPCRs…) signaling cascades, combined with the spatiotemporal control of endogenous ligands, will result in effective therapeutics with fewer side effects.