From HTS to Market: the Discovery and Development of Maraviroc, a CCR5 Antagonist for the Treatment of HIV - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 185

Figure 9.1 HIV viral life-cycle. Reproduced with permission from Weiss. 7

internalisation would need to occur before significant receptor signalling, and
this has yet to be demonstrated in vivo.

9.3 CC Chemokine Receptor 5
CC Chemokine receptor 5 (CCR5) is a member of the GPCRs (G protein-
coupled receptors), which are targets for 30% of marketed drugs. This obser-
vation suggests that it should be possible to develop small-molecule antagonists
to CCR5. 15 The three extracellular loops (ECLs 1-3) together with the N-ter-
minus are the targets for chemokine binding and for interactions with the viral
gp120 protein. The three intracellular loops and C-terminus participate in G
protein-mediated signal transduction. CCR5 is expressed on the cell surface of
a wide range of cell types, predominantly on T cells, macrophages, microglia
and dendritic cells. 16 To date, it has been found to bind to a number of different
chemokines (MIP1a, MIP1b, MCP-2, RANTES, MCP3 and MCP4), but only
MIP1b is selective for CCR5. 17 Activation of CCR5 results in a number of
typical GPCR responses, including Ca 21 release and cAMP production, which
result in the activation and tracking of leukocytes to sites of inflammation. 18
There is no X-ray structural information for CCR5, although many groups
have proposed homology models based upon the crystal structure of

rhodopsin. 19