title: Structure-Activity Relationship and Signaling of New Chimeric CXCR4 Agonists.
abstract: 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.
authors.affiliation: 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.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Mona
authors.affiliation: 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.
authors.forename: Élie
authors.initials: É
authors.lastname: Besserer-Offroy
authors.affiliation: 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.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cabana
authors.affiliation: 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.
authors.forename: Marilou
authors.initials: M
authors.lastname: Lefrançois
authors.affiliation: 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.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Boulais
authors.affiliation: 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.
authors.forename: Marie-Reine
authors.initials: MR
authors.lastname: Lefebvre
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Leduc
authors.affiliation: Department of Biochemistry, Université de Sherbrooke , Sherbrooke, QC J1H 5N4, Canada.|Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke , Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lavigne
authors.affiliation: Department of Biochemistry and Molecular Medicine, Centre de recherche du CHU Sainte-Justine, Université de Montréal , Montréal, QC H3T 1C4, Canada.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Heveker
authors.affiliation: 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.
authors.forename: Éric
authors.initials: É
authors.lastname: Marsault
authors.affiliation: 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.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Escher
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: C527276:CXCR4 protein, human; D010455:Peptides; D019718:Receptors, CXCR4