CXCR4 as a novel target in immunology: moving away from typical antagonists

Abstract

CXCR4 has been a target of interest in drug discovery for numerous years. However, so far, most if not all studies focused on finding antagonists of CXCR4 function. Recent studies demonstrate that targeting a minor allosteric pocket of CXCR4 induces an immunomodulating effect in immune cells expressing CXCR4, connected to the TLR pathway. Compounds binding in this minor pocket seem to be functionally selective with inverse agonistic properties in selected GPCR signaling pathways (G_i activation), but additional signaling pathways are likely to be involved in the immunomodulating effects. In depth research into these CXCR4-targeted immunomodulators could lead to novel treatment options for (auto)-immune diseases.

Keywords: GPCR; drug design; immunology; small molecule.

Figure 1.. Selected small molecule CXCR4 ligands.

Structure of small molecules activating a CXCR4 dependent anti-inflammatory effect (A–E) through binding into the minor pocket of CXCR4. Minor pocket ligands: (A) dopamine, (B) serotonin, (C) histamine, (D) clobenpropit (CB) and (E) IT1t. (F) Structure of small molecule antagonist AMD3100.

Figure 2.. CXCR4 blocks TLR activation. Activation of TLRs and their down-steam signaling ultimately results in elevated type-I interferons.

This is initiated by pathogens but can also be chronically elevated in auto-immune disease. Novel CXCR4 minor pocket ligands cause inhibition of TLR downstream signaling and subsequent reduction of interferon type-I levels, the exact mode of action remains unclear.

Figure 3.. Comparison of binding sites at

CXCR 4. Key interaction partners of IT1t are highlighted in red [39], key residues interacting with AMD3100 are highlighted in blue [41,57] and shared residues in purple. (A) top view of the receptor and (B) snake plot of CXCR4. CXCR4 plots adapted from GPCRdb [58].

Figure 4.. Hypothetical signalling of IT1t at CXCR4.

IT1t has been published to inhibit G_i2 signaling. Hypothetical signaling promoted further downstream at CXCR4 by IT1t and potentially other minor pocket ligands include the cAMP, PI3K/Akt and MAPK pathway; several of these pathways have been shown to regulate inflammation.