Molecular determinants of antagonist interactions with chemokine receptors CCR2 and CCR5.

Abstract

CC chemokine receptors 2 and 5 (CCR2 and CCR5) are GPCRs that guide monocytes towards regions of inflammation, thus shaping the inflammatory response. CCR2 & CCR5 have been extensively studied as potential targets in Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH), where antagonizing CCR2 reduces Kupffer cell activation, lowers monocyte infiltration, and prevents liver fibrosis. In the case of pancreatic ductal adenocarcinoma (PDAC), a lethal cancer, CCR2-mediated macrophage infiltration of the tumor microenvironment leads to poor patient survival and increased resistance to chemo-, radiation, and immuno-therapies, thus motivating studies of CCR2 antagonists in combination with these therapies. However, no CCR2 antagonist has yet reached the clinic. Redundancies inherent to the chemokine system make targeting this receptor difficult. Many inhibitors of CCR2 have comparable affinity for CCR5; while dual-selective CCR2/CCR5 antagonists may be indicated for NASH, dual-selectivity hinders their use for PDAC. To guide the design of better CCR2- and CCR5-targeting small-molecule therapeutics, it is necessary to understand the structural basis of antagonist interaction with these highly homologous receptors.