Broad spectrum chemokine inhibitors related to NR58-3.14.3.

ABSTRACT

The chemokine family consists of more than 50 structurally-related small proteins which signal through type 1 G-protein coupled receptors (GPCRs) to regulate a range of immune functions, with particular focus on regulating leukocyte trafficking. They have been implicated both in normal physiological leukocyte traffic, and in recruitment of leukocytes to sites of pathological inflammation. As a result, chemokine inhibitors may have useful anti-inflammatory therapeutic properties in vivo. Compounds with chemokine-inhibitory properties that have been described to date, fall into two broad categories receptor-specific antagonists which block the action of one or a small number of related chemokines, and broad-spectrum chemokine inhibitors (BSCIs) which block leukocyte migration in response to many, if not all, chemokines simultaneously. Since many chemokines apparently show functional redundancy in vivo, the BSCI class are attractive candidates for development as anti-inflammatory therapies. Here, we review the development of BSCIs, with particular focus on the design and characterisation of non-peptide compounds. The key structural requirements for BSCI activity are discussed, together with their implications for the mechanism of BSCI action.