Posted May 20, 2015
Brian Zabel, Ph.D., VA Palo Alto Health Care System
In multiple sclerosis (MS), immune cells migrate to the brain and attack the myelin insulation that coats nerve fibers. The migration of the immune cells is controlled by small molecules known as "chemoattractants" that activate receptor proteins located on the surface of immune cells. Previous research had demonstrated that a chemoattractant called "chemerin" and its receptor called "chemokine-like receptor 1" (CMKLR1) both accumulate in brain lesions of MS patients.
With funding from an FY10 Idea Award, Dr. Brian Zabel tested the hypothesis that blocking the interaction between chemerin and its receptor will inhibit immune cell migration to the brain and might prove useful for the treatment of MS. He screened a library of 130,000 different compounds to identify drugs that inhibit the interaction between chemerin and its receptor, CMKLR1. He identified a small molecule, 2-(α-naphthoyl) ethyltrimethyl ammonium iodide (α-NETA) that inhibited the ability of chemerin to activate its receptor CMKLR1 and demonstrated that this drug prevents immune cell migration. To determine if α-NETA might be effective in treating MS, he used the widely studied experimental autoimmune encephalomyelitis (EAE) mouse model that shares many features with human MS including accumulation of chemerin and CMKLR1 in brain and spinal cord lesions. He found that prolonged administration of α-NETA significantly delayed onset of clinical EAE (e.g. limb weakness and paralysis) and limited immune cell infiltrates in the brain.
Although mice treated long term with α-NETA eventually developed EAE symptoms, this study provides proof-of-concept that targeting the interaction of chemerin with its receptor may be beneficial in preventing or treating MS. However, Dr. Zabel says, "The complexity and heterogeneity of MS poses challenges for attaining desirable clinical outcomes by targeting a single chemoattractant receptor." He further suggested that "MS treatments that inhibit CMKLR1 or other candidate receptors as part of a 'polypharmacologic' approach may be more efficacious than targeting a single receptor".
Graham KL, Zhang JV, Lewén S, Burke TM, Dang T, Zoudilova M, Sobel RA, Butcher EC, Zabel BA. A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease. PLoS One. 2014 Dec 1;9(12):e112925.