Ligand-selective small molecule modulators of the constitutively active vGPCR US28

• Published in: European journal of medicinal chemistry 2018-07, Vol.155, p.244-254
• Main Authors: Amărandi, Roxana-Maria, Lückmann, Michael, Melynis, Motiejus, Jakobsen, Mette H., Fallah, Zohreh, Spiess, Katja, Hjortø, Gertrud M., Pui, Aurel, Frimurer, Thomas M., Rosenkilde, Mette M.
• Format: Article
• Language: English
• Subjects: Drug discovery; G protein-coupled receptor; Molecular modeling; Virtual screening
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.05.053

US28 is a broad-spectrum constitutively active G protein-coupled receptor encoded by the human cytomegalovirus (HCMV). It binds and scavenges multiple CC-chemokines as well as CX3CL1 (fractalkine) by constitutive receptor endocytosis to escape immune surveillance. We herein report the design and characterization of a novel library of US28-acting commercially available ligands based on the molecular descriptors of two previously reported US28-acting structures. Among these, we identify compounds capable of selectively recognizing CCL2-and CCL4-, but not CX3CL1-induced receptor conformations. Moreover, we find a direct correlation between the binding properties of small molecule ligands to CCL-induced conformations at the wild-type receptor and functional activity at the C-terminal truncated US28Δ300. As US28Δ300 is devoid of arrestin-recruitment and endocytosis, this highlights the potential usefulness of this construct in future drug discovery efforts aimed at specific US28 conformations. The new scaffolds identified herein represent valuable starting points for the generation of novel anti-HCMV therapies targeting the virus-encoded chemokine receptor US28 in a conformational-selective manner. [Display omitted] •A novel library of US28-acting ligands was designed and characterized.•Ligands recognize CCL2-and CCL4-, but not CX3CL1-induced receptor conformations.•Constitutive internalization of US28 camouflages ligand activity.•Ligand binding behavior correlates with activity at truncated US28Δ300 construct.