Biased agonism at chemokine receptors: obstacles or opportunities for drug discovery?

Chemokine receptors are typically promiscuous, binding more than one ligand, with the ligands themselves often expressed in different spatial localizations by multiple cell types. This is normally a tightly regulated process; however, in a variety of inflammatory disorders, dysregulation results in the excessive or inappropriate expression of chemokines that drives disease progression. Biased agonism, the phenomenon whereby different ligands of the same receptor are able to preferentially activate one signaling pathway over another, adds another level of complexity to an already complex system. In this minireview, we discuss the concept of biased agonism within the chemokine family and report that targeting single signaling axes downstream of chemokine receptors is not only achievable, but may well present novel opportunities to target chemokine receptors, allowing the fine tuning of receptor responses in the context of allergic inflammation and beyond.