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“School of Nano-Sciences”

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Paper   IPM / Nano-Sciences / 15284
School of Nano Science
  Title:   Ligand-selective small molecule modulators of the constitutively active vGPCR US28
  Author(s): 
1 . Roxana-Maria Amarandi
2 . Michael Lückmann
3 . Motiejus Melynis
4 . Mette H. Jakobsen
5 . Zohreh Fallah
6 . Katja Spiess
7 . Gertrud M. Hjortø
8 . Aurel Pui
9 . Thomas M. Frimurer
10 . Mette M. Rosenkilde
  Status:   Published
  Journal: European Journal of Medicinal Chemistry
  Vol.:  155
  Year:  2018
  Pages:   244
  Publisher(s):   Elsevier
  Supported by:  IPM
  Abstract:
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 US28�?300. As US28�?300 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.

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