Exploring the CXCR3 Chemokine Receptor with Small-Molecule Antagonists and Agonists

CXCR3 is a CXC chemokine receptor that, together with its three major ligands, CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC), is involved in inflammatory responses, mediated mainly by T cells. In several immune-related diseases, including chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), rheumatoid arthritis, multiple sclerosis, and atherosclerosis, CXCR3 and/or its ligands are found to be overexpressed, potentially indicating a role for this receptor in these diseases. Animal models have confirmed the therapeutic potential of targeting CXCR3 in the treatment of such diseases. Several peptidic, peptidomimetic, and small non-peptidomimetic CXCR3 ligands have been disclosed in the past 10 years. These ligands have served as chemical tools for the investigation of CXCR3 activation, blocking, and signaling, and some of these ligand series have been developed as potential therapeutic agents against inflammation. Computational modeling studies, facilitated by the recent developments in GPCR structural biology, together with mutagenesis and pharmacological studies, have aided in understanding how these ligands interact with CXCR3.