A novel CMKLR1 small molecule antagonist suppresses experimental autoimmune demyelinating disease (P5179)

Abstract

Abstract Experimental autoimmune encephalomyelitis (EAE) is a widely studied mouse model that shares many clinical and histological features with multiple sclerosis (MS). Chemokine-like receptor-1 (CMKLR1) is a chemoattractant receptor that is expressed by key effector leukocytes in EAE and MS, including macrophages, subsets of dendritic cells, and natural killer cells. We previously showed that clinical and histological EAE is less severe in CMKLR1-deficient (CMKLR1 KO) mice compared with wild-type. In this study, we sought to identify small molecular CMKLR1 inhibitors that recapitulate the CMKLR1 KO phenotype in EAE. We identified α-naphthoyl ethyltrimethylammonium iodide (α-NETA) as a selective CMKLR1 small molecule antagonist that inhibits chemerin-stimulated β-arrestin2 association with CMKLR1, as well as chemerin-triggered CMKLR1+ cell migration. Structure-activity relationship studies indicated that the trimethylamine region is critical for CMKLR1 potency. Prophylactic dosing with α-NETA (i.e. prior to the onset of clinical signs) significantly delayed the onset of EAE induced in C57BL/6 mice by active immunization with myelin oligodendrocyte glycoprotein peptide 35-55. In addition, α-NETA treatment significantly reduced mononuclear cell infiltrates within the CNS. This study provides proof-of-concept data that pharmaceutical targeting of CMKLR1:chemerin interactions may be beneficial in preventing or treating MS.