CCR5 antagonists: from discovery to clinical efficacy

CCR5 is a prototypically inflammatory chemokine receptor belonging to the seven transmembrane G-protein-coupled receptor (GPCR) family. This family is generally considered druggable and well represented in marketed drugs [ 1 ]–[ 6 ]. The CCR5 receptor is expressed on numerous host defense cells including monocytes, macrophages, T-lymphocytes, dendritic cells and microglia [ 4 , 5 ]. Interaction of CCR5 with its ligands MIP-1α, MIP-1β (CCL3/CCL4) or RANTES (CCL5) results in a conformational change in the seven transmembrane domain initiating a signaling cascade through heterotrimeric G-proteins ultimately giving rise to migration of immune cells to sites of inflammation [ 2 , 5 ]. Due to the well documented role of CCR5 in the immune system, it has been implicated in the pathophysiology of rheumatoid arthritis (RA), multiple sclerosis (MS), transplant rejection, gastric disorders, diabetes and myeloma [ 7 ]. Perhaps the biggest driver behind the development of CCR5 receptor antagonists was the discovery that CCR5 plays an important role as a co-receptor for macrophage tropic HIV-1 strains to facilitate viral fusion and entry into host cells [ 5 ], [ 8 ]–[ 12 ]. In addition, individuals with a mutation in the CCR5 gene (CCR5Δ32) lacking expression of CCR5 on the cell surface are resistance to HIV-1 infection without notable immune system effects [ 13 , 14 ], thus validating pharmaceutical intervention with a CCR5 antagonist. These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.