Ligand-Based NMR Study of C-X-C Chemokine Receptor Type 4 (CXCR4)-Ligand Interactions on Living Cancer Cells

Diego Brancaccio, Donatella Diana, Salvatore Di Maro, Francesco Saverio Di Leva, Stefano Tomassi, Roberto Fattorusso, Stefania Scala, Anna Maria Trotta, Luigi Portella, Ettore Novellino, Luciana Marinelli, Alfonso Carotenuto

Research output: Contribution to journalArticle

Abstract

Peptide-binding G protein-coupled receptors (GPCRs) are key effectors in numerous pathological and physiological pathways. The assessment of the receptor-bound conformation of a peptidic ligand within a membrane receptor such as a GPCR is of great impact for a rational drug design of more potent analogues. In this work, we applied multiple ligand-based nuclear magnetic resonance (NMR) methods to study the interaction of peptide heptamers, derived from the C-X-C Motif Chemokine 12 (CXCL12), and the C-X-C Chemokine Receptor Type 4 (CXCR4) on membranes of human T-Leukemia cells (CCRF-CEM cells). This study represents the first structural investigation reporting the receptor-bound conformation of a peptide to a GPCR directly on a living cell. The results obtained in the field of CXCL12/CXCR4 are proofs of concept, although important information for researchers dealing with the CXCR4 field arises. General application of the presented NMR methodologies is possible and surely may help to boost the development of new therapeutic agents targeting GPCRs.

Original languageEnglish
Pages (from-to)2910-2923
Number of pages14
JournalJournal of Medicinal Chemistry
Volume61
Issue number7
DOIs
Publication statusPublished - Apr 12 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Brancaccio, D., Diana, D., Di Maro, S., Di Leva, F. S., Tomassi, S., Fattorusso, R., Scala, S., Trotta, A. M., Portella, L., Novellino, E., Marinelli, L., & Carotenuto, A. (2018). Ligand-Based NMR Study of C-X-C Chemokine Receptor Type 4 (CXCR4)-Ligand Interactions on Living Cancer Cells. Journal of Medicinal Chemistry, 61(7), 2910-2923. https://doi.org/10.1021/acs.jmedchem.7b01830