Unravelling the mechanisms underpinning chemokine receptor activation and blockade by small molecules: a fine line between agonism and antagonism?
Chemokines are a family of small basic proteins which induce the directed migration of cells, notably leucocytes, by binding to specific GPCRs (G-protein-coupled receptors). Both chemokines and their receptors have been implicated in a host of clinically important diseases, leading to the notion that antagonism of the chemokine-chemokine receptor network may be therapeutically advantageous. Consequently, considerable effort has been put into the development of small-molecule antagonists of chemokine receptors and several such compounds have been described in the literature. One curious by-product of this activity has been the description of several small-molecule agonists of the receptors, which are typically discovered following the optimization of lead antagonists. In this review we discuss these findings and conclude that these small-molecule agonists might be exploited to further our understanding of the molecular mechanisms by which chemokine receptors are activated.
Wise
E
E
Leukocyte Biology Section, NHLI Division, Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. e.wise@imperial.ac.uk
Pease
J E
JE
D000818:Animals; D006801:Humans; D019707:Receptors, Chemokine / Q000819:agonists* / Q000037:antagonists & inhibitors*
D019707:Receptors, Chemokine