High-affinity ELR+ chemokine ligands show G protein bias over β-arrestin recruitment and receptor internalization in CXCR1 signaling.

The human CXC chemokine receptor 1 (CXCR1), a G protein-coupled receptor (GPCR), plays significant roles in inflammatory diseases and cancer. While CXCL8 is a well-established high-affinity ligand for CXCR1, there is no consensus regarding the binding ability of the other ELR+ chemokines (CXCL1-3 and CXCL5-8). Since research has predominantly focused on CXCL8-mediated CXCR1 signaling, insight into potential signaling bias induced by different CXCR1 ligands is lacking.

Systematic Assessment of Human CCR7 Signalling Using NanoBRET Biosensors Points towards the Importance of the Cellular Context.

The human CC chemokine receptor 7 (CCR7) is activated by two natural ligands, CC chemokine ligand 19 (CCL19) and 21 (CCL21). The CCL19-CCL21-CCR7 axis has been extensively studied in vitro, but there is still debate over whether CCL21 is an overall weaker agonist or if the axis displays biased signalling. In this study, we performed a systematic analysis at the transducer level using NanoBRET-based methodologies in three commonly used cellular backgrounds to evaluate pathway and ligand preferences, as well as ligand bias and the influence of the cellular system thereon.

Systematic assessment of chemokine ligand bias at the human chemokine receptor CXCR2 indicates G protein bias over β-arrestin recruitment and receptor internalization.

Background: The human CXC chemokine receptor 2 (CXCR2) is a G protein-coupled receptor (GPCR) interacting with multiple chemokines (i.e., CXC chemokine ligands CXCL1-3 and CXCL5-8).

REGA-SIGN: Development of a Novel Set of NanoBRET-Based G Protein Biosensors.

Despite G protein-coupled receptors (GPCRs) being important theapeutic targets, the signaling properties of many GPCRs remain poorly characterized. GPCR activation primarily initiates heterotrimeric G protein signaling. To detect ligand-induced G protein activation, Bioluminescence Resonance Energy Transfer (BRET)-based biosensors were previously developed.

Exploration of Pyrido[3,4-]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2.

Upregulated CXCR2 signalling is found in numerous inflammatory, autoimmune and neurodegenerative diseases, as well as in cancer. Consequently, CXCR2 antagonism is a promising therapeutic strategy for treatment of these disorders. We previously identified, via scaffold hopping, a pyrido[3,4-]pyrimidine analogue as a promising CXCR2 antagonist with an IC value of 0.

Cellular Electrical Impedance as a Method to Decipher CCR7 Signalling and Biased Agonism.

The human C-C chemokine receptor type 7 (CCR7) has two endogenous ligands, C-C chemokine ligand 19 (CCL19) and CCL21, displaying biased agonism reflected by a pronounced difference in the level of β-arrestin recruitment. Detecting this preferential activation generally requires the use of separate, pathway-specific label-based assays. In this study, we evaluated an alternative methodology to study CCR7 signalling.

Identification of novel chemotypes as CXCR2 antagonists via a scaffold hopping approach from a thiazolo[4,5-d]pyrimidine.

The chemokine receptor CXCR2 and its ligands mediate neutrophil migration to the inflammation site, function as growth factors in many tumor cells and are involved in angiogenesis. Moreover, CXCR2 mediated recruitment of myeloid-derived suppressor cells results in tumor immunosuppression. Consequently, CXCR2 antagonism is a promising strategy for cancer immunotherapy and treatment of inflammatory disorders.