title: A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease.
abstract: Therapies that target leukocyte trafficking pathways can reduce disease activity and improve clinical outcomes in multiple sclerosis (MS). Experimental autoimmune encephalomyelitis (EAE) is a widely studied animal model that shares many clinical and histological features with MS. Chemokine-like receptor-1 (CMKLR1) is a chemoattractant receptor that is expressed by key effector cells in EAE and MS, including macrophages, subsets of dendritic cells, natural killer cells and microglia. We previously showed that CMKLR1-deficient (CMKLR1 KO) mice develop less severe clinical and histological EAE than wild-type mice. In this study, we sought to identify CMKLR1 inhibitors that would pharmaceutically recapitulate the CMKLR1 KO phenotype in EAE. We identified 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) as a CMKLR1 small molecule antagonist that inhibits chemerin-stimulated β-arrestin2 association with CMKLR1, as well as chemerin-triggered CMKLR1+ cell migration. α-NETA significantly delayed the onset of EAE induced in C57BL/6 mice by both active immunization with myelin oligodendrocyte glycoprotein peptide 35-55 and by adoptive transfer of encephalitogenic T cells. In addition, α-NETA treatment significantly reduced mononuclear cell infiltrates within the CNS. This study provides additional proof-of-concept data that targeting CMKLR1:chemerin interactions may be beneficial in preventing or treating MS.
authors.affiliation: Palo Alto Veterans Institute for Research and Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Kareem L
authors.initials: KL
authors.lastname: Graham
authors.affiliation: Palo Alto Veterans Institute for Research and Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Jian V
authors.initials: JV
authors.lastname: Zhang
authors.affiliation: Palo Alto Veterans Institute for Research and Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Susanna
authors.initials: S
authors.lastname: Lewén
authors.affiliation: Palo Alto Veterans Institute for Research and Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Burke
authors.affiliation: ChemoCentryx, Inc., Mountain View, California, United States of America.
authors.forename: Ton
authors.initials: T
authors.lastname: Dang
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Zoudilova
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Butcher
authors.affiliation: Palo Alto Veterans Institute for Research and Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Zabel
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000644:Quaternary Ammonium Compounds / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D012449:Safety; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C486456:CMKLR1 protein, mouse; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; D009281:Naphthalenes; D000644:Quaternary Ammonium Compounds; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C523686:chemerin protein, mouse; C055734:2-naphthoylethyltrimethylammonium