CCR5 antagonists: the answer to inflammatory disease?

Abstract

Chemokines and their receptors mediate the inflammatory response during infectious and non-infectious disease. However, their continued activation and disregulation are commonly associated with chronic inflammation. Frequently, affected sites are characterised by inflammatory cell infiltrates expressing CC chemokine receptor 5 (CCR5) and high levels of CCR5 ligands. Neutralisation of CCR5 decreases the incidence and pathology of these diseases in murine models, and epidemiological studies in human patients corroborate these data. CCR5-deficiency has been associated with increased risk of hepatic disease and infection, but considering the pathological effects of chronic inflammation, pharmacologically targeting CCR5 is still a desirable and feasible goal. The discovery that CCR5 is a major HIV coreceptor initiated the race to produce effective CCR5 antagonists. This review summarises the progress made in CCR5 antagonist development and assesses their potential in the treatment of inflammatory disease.

Keywords::

• CCR5
• chemokine
• chemokine receptor
• Met-RANTES
• SCH-C
• SCH-D
• small molecule antagonist
• TAK-779
• UK-427,857

Acknowledgements

The authors thank NS Green for invaluable assistance with drawing the chemical structures of the CCR5 antagonists.