title: Partial Agonist and Biased Signaling Properties of the Synthetic Enantiomers J113863/UCB35625 at Chemokine Receptors CCR2 and CCR5.
abstract: Biased agonism at G protein-coupled receptors constitutes a promising area of research for the identification of new therapeutic molecules. In this study we identified two novel biased ligands for the chemokine receptors CCR2 and CCR5 and characterized their functional properties. We showed that J113863 and its enantiomer UCB35625, initially identified as high affinity antagonists for CCR1 and CCR3, also bind with low affinity to the closely related receptors CCR2 and CCR5. Binding of J113863 and UCB35625 to CCR2 or CCR5 resulted in the full or partial activation of the three Giproteins and the two Goisoforms. Unlike chemokines, the compounds did not activate G12Binding of J113863 to CCR2 or CCR5 also induced the recruitment of β-arrestin 2, whereas UCB35625 did not. UCB35625 induced the chemotaxis of L1.2 cells expressing CCR2 or CCR5. In contrast, J113863 induced the migration of L1.2-CCR2 cells but antagonized the chemokine-induced migration of L1.2-CCR5 cells. We also showed that replacing the phenylalanine 3.33 in CCR5 TM3 by the corresponding histidine of CCR2 converts J113863 from an antagonist for cell migration and a partial agonist in other assays to a full agonist in all assays. Further analyses indicated that F3.33H substitution strongly increased the activation of G proteins and β-arrestin 2 by J113863. These results highlight the biased nature of the J113863 and UCB35625 that act either as antagonist, partial agonist, or full agonist according to the receptor, the enantiomer, and the signaling pathway investigated.
authors.affiliation: From the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM) Université Libre de Bruxelles (ULB), Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium and.
authors.forename: Jenny
authors.initials: J
authors.lastname: Corbisier
authors.affiliation: From the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM) Université Libre de Bruxelles (ULB), Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium and.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Huszagh
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, INSERM, Université Toulouse III Paul Sabatier, 31432 Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Galés
authors.affiliation: From the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM) Université Libre de Bruxelles (ULB), Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium and.
authors.forename: Marc
authors.identifier: http://orcid.org/0000-0001-6553-2786
authors.initials: M
authors.lastname: Parmentier
authors.affiliation: From the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM) Université Libre de Bruxelles (ULB), Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium and jyspring@ulb.ac.be.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Springael
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D002465:Cell Movement / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D011485:Protein Binding / Q000187:drug effects; D054390:Receptors, CCR2 / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014966:Xanthenes / Q000737:chemistry / Q000494:pharmacology*; D000071560:beta-Arrestin 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C000605254:ARRB2 protein, human; C515334:CCR2 protein, human; C584933:CCR5 protein, human; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D014966:Xanthenes; D000071560:beta-Arrestin 2; C413447:UCB 35625; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
keywords: C-C chemokine receptor type 5 (CCR5); G protein-coupled receptor (GPCR); biased agonist; chemokine; drug action; drug discovery; signaling