Biology subjects

Meyrath, M.

Publications and source records attributed to Meyrath, M..

3 recordsLinked to original sources

bioRxiv2024

Inhibition of constitutive activity of the atypical chemokine receptor ACKR3 by the small-molecule inverse agonist VUF16840

The atypical chemokine receptor 3 (ACKR3) has emerged as a promising drug target for the treatment of cancer, cardiovascular, and autoimmune diseases. In this study, we present the pharmacological characterization of VUF16840, the first small-molecule inverse agonist of ACKR3. VUF16840 effectively displaces CXCL12 binding to ACKR3 and inhibits chemokine-induced {beta}-arrestin2 recruitment in a concentration-dependent manner. Furthermore, VUF16840 stabilizes the inactive conformation of ACKR3, as demonstrated by its ability to suppress constitutive {beta}-arrestin2 recruitment. This inverse agonism alters ACKR3 constitutive trafficking, leading to receptor enrichment at the plasma membrane and inhibition of intracellular CXCL12 uptake. Importantly, VUF16840 exhibits high selectivity for ACKR3 over a broad panel of human chemokine receptors. These findings establish VUF16840 as a potent and selective ACKR3 inverse agonist capable of modulating constitutive and chemokine-induced signaling and internalization events. As such, VUF16840 represents a valuable pharmacological tool for exploring the molecular and translational roles of ACKR3 in both physiological and pathological contexts.

pharmacology and toxicology↗

bioRxiv2024

ACKR5/GPR182 is a scavenger receptor for the atypical chemokine CXCL17, GPR15L and various endogenous peptides

GPR182/ACKR5, the most recently deorphanized chemokine receptor, is mainly expressed on endothelial cells and was proposed to act as a scavenger regulating the availability of a large set of chemokines. In this study, we first established the exact profiles and ranking of the chemokines binding to the human and mouse GPR182. We confirmed the high promiscuity of GPR182 towards XC, CC and CXC chemokines and a clear difference in the chemokine repertoires of the human and mouse orthologues. We next demonstrated that, beyond classical chemokines, GPR182 exhibits potent binding to the chemoattractant protein GPR15L/C10orf99, the atypical chemokine CXCL17 and various endogenous peptides, mainly from the opioid, apelin, and PACAP families. We also showed that these newly identified ligands engage GPR182 through varied binding modes. While GPR15L, just like classical chemokines, predominantly engages GPR182 via its N terminus, conversely to the C terminus-dependent binding to its cognate receptor GPR15, CXCL17 exhibits a more complex interaction, relying on both the N and C terminus. The binding mode of the newly identified peptide ligands also differ from the interactions with their cognate receptors. Our findings establish the first scavenger receptor for CXCL17 and GPR15L and advance the understanding of GPR182 ligand interactions, suggesting a regulatory role beyond chemokines.

pharmacology and toxicology↗

bioRxiv2023

Pharmacological characterization and radiolabeling ofVUF15485, a high-affinity small-molecule agonist for theatypical chemokine receptor ACKR3

Atypical chemokine receptor 3 (ACKR3), formerly referred to as CXCR7, is considered to be an interesting drug target. In this study we report on the synthesis, pharmacological characterization and radiolabeling of VUF15485, a new ACKR3 small-molecule agonist, that will serve as an important new tool to study this {beta}-arrestin-biased chemokine receptor. VUF15485 binds with nanomolar affinity (pIC50 = 8.3) to human ACKR3, as measured in [125I]CXCL12 competition binding experiments. Moreover, in a BRET-based {beta}-arrestin2 recruitment assay VUF15485 acts as an ACKR3 agonist with high potency (pEC50 = 7.6) and shows a similar extent of receptor activation compared to CXCL12 when using a newly developed, FRET-based ACKR3 conformational sensor. Moreover, the ACKR3 agonist VUF15485 was tested against a (atypical) chemokine receptor panel (agonist and antagonist mode) and proves to be selective for ACKR3. VUF15485 was subsequently labeled with tritium at one of its methoxy groups affording [3H]VUF15485. The small-molecule agonist radioligand binds saturably and with high affinity to human ACKR3 (Kd = 8.2 nM). [3H]VUF15485 shows rapid binding kinetics and consequently a short residence time (RT < 2 min) for its binding to ACKR3. Displacement of [3H]VUF15485 binding to membranes of HEK293T cells, transiently expressing ACKR3, with a number of CXCR3, CXCR4 or ACKR3 small-molecule ligands confirmed the ACKR3 profile of the [3H]VUF15485 binding site. Interestingly, the chemokine ligands CXCL11 and CXCL12 are not able to displace the binding of [3H]VUF15485 to ACKR3. The radiolabeled VUF15485 was subsequently used to evaluate its binding pocket. Site-directed mutagenesis and docking studies using a recently solved cryo-EM structure propose VUF15485 to bind in the major and the minor binding pocket of ACKR3.

pharmacology and toxicology↗