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

Abstract

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.

A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2–mediated inflammation

“…Notably, it remains unclear how CCL1 and CCL8 differentially regulate the fate of ILC2s and other CCR8-expressing cells. However, such functional selectivity has been observed for other important chemokine receptor ligands (Anderson et al, 2016) and may in the case of CCR8 be exploited for targeted therapy of type 2-mediated diseases.…”

Biased Receptor Signaling in Drug Discovery

“…Specifically, four natural agonists for this receptor (CXCL4, CXCL9, CXCL10, and CXCL11) demonstrate very different biased signaling (with respect to G protein vs. b-arrestin) on these variants to affect cell-based signaling selectivity (Berchiche and Sakmar, 2016). The chemokine system is currently an active target for drug discovery and strategies employing biased signaling are under investigation (Amarandi et al, 2016;Anderson et al, 2016;Roy et al, 2017). Another multiple natural agonist system involves the Class Frizzled (FZD1-10) receptors activated by the WNT family of lipoglycoproteins; these endogenous ligands are shown to have natural bias toward different downstream signaling pathways producing functional selectivity within a complex network of signaling pathways (Dijksterhuis et al, 2015) Finally, although there is evidence for biased signaling within collections of natural multiple endogenous agonists, this mechanism also is operable for metabolites of natural agonists to produce modified signaling after agonist metabolism.…”

Mu-Opioid receptor biased ligands: A safer and painless discovery of analgesics?

“…The discovery of molecules with the ability to selectively modulate GPCRs has been described extensively in the literature [27,29–34], supporting and validating the discovery of emerging functionally selective drugs. The increasing number of biased GPCR agonists with potential therapeutic impact is remarkable, as summarized in Table 1.…”