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

journal contribution
posted on 30.03.2021, 12:46 authored by Roxana-Maria Amărandi, Michael Lückmann, Motiejus Melynis, Mette H Jakobsen, Zohreh FallahZohreh Fallah, Katja Spiess, Gertrud M Hjortø, Aurel Pui, Thomas M Frimurer, Mette M Rosenkilde
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 CCLinduced conformations at the wild-type receptor and functional activity at the C-terminal truncated US28D300. As US28D300 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

Funding

Novo Nordisk Foundation Center for Basic Metabolic Research (NNF10CC1016515)

Novo Nordisk Foundation Center for Protein Research (NNF14CC0001)

Danish Council for Independent Research (DFF-5053-00276)

History

School

  • Science

Department

  • Materials

Published in

European Journal of Medicinal Chemistry

Volume

155

Pages

244 - 254

Publisher

Elsevier BV

Version

VoR (Version of Record)

Rights holder

© Elsevier

Acceptance date

30/05/2018

Publication date

2018-05-31

Copyright date

2018

ISSN

0223-5234

Language

en

Depositor

Dr Zohreh Fallah. Deposit date: 25 March 2021