Mona Christine E, Besserer-Offroy Élie, Cabana Jérôme, Lefrançois Marilou, Boulais Philip E, Lefebvre Marie-Reine, Leduc Richard, Lavigne Pierre, Heveker Nikolaus, Marsault Éric, Escher Emanuel
Department of Pharmacology-Physiology, Université de Sherbrooke , Sherbrooke, QC J1H 5N4, Canada.
Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke , Sherbrooke, QC J1H 5N4, Canada.
J Med Chem. 2016 Aug 25;59(16):7512-24. doi: 10.1021/acs.jmedchem.6b00566. Epub 2016 Aug 11.
The CXCR4 receptor binds with meaningful affinities only CXCL12 and synthetic antagonists/inverse agonists. We recently described high affinity synthetic agonists for this chemokine receptor, obtained by grafting the CXCL12 N-terminus onto the inverse agonist T140. While those chimeric molecules behave as agonists for CXCR4, their binding and activation mode are unknown. The present SAR of those CXCL12-oligopeptide grafts reveals the key determinants involved in CXCR4 activation. Position 3 (Val) controls affinity, whereas position 7 (Tyr) acts as an efficacy switch. Chimeric molecules bearing aromatic residues in position 3 possess high binding affinities for CXCR4 and are Gαi full agonists with robust chemotactic properties. Fine-tuning of electron-poor aromatic rings in position 7 enhances receptor activation. To rationalize these results, a homology model of a receptor-ligand complex was built using the published crystal structures of CXCR4. Molecular dynamics simulations reveal further details accounting for the observed SAR for this series.
