Emerging concepts and approaches for chemokine-receptor drug discovery.
BACKGROUND
Chemokine receptors are most noted for their role in cell migration. However, inappropriate utilization or regulation of these receptors is implicated in many inflammatory diseases, cancer and HIV, making them important drug targets.


METHODS
Allostery, oligomerization and ligand bias are presented as they pertain to chemokine receptors and their associated pathologies.Specific examples of each are described from the recent literature and their implications are discussed in terms of drug discovery efforts targeting chemokine receptors.


RESULTS
Insight into the expanding view of the multitude of pharmacological variables that need to be considered or that may be exploited in chemokine receptor drug discovery.


CONCLUSIONS
Since 2007, two drugs targeting chemokine receptors have been approved by the FDA, Maraviroc for preventing HIV infection and Mozobil™ for hematopoietic stem cell mobilization. While these successes permit optimism for chemokine receptors as drug targets, only recently has the complexity of this system begun to be appreciated. The concepts of allosteric inhibitors, biased ligands and functional selectivity raise the possibility that drugs with precisely-defined properties can be developed. Other complexities such as receptor oligomerization and tissue-specific functional states of receptors also offer opportunities for increased target and response specificity, although it will be more challenging to translate these ideas into approved therapeutics compared to traditional approaches.
University of California, San Diego, Skaggs School of Pharmacy andPharmaceutical Sciences, La Jolla, CA 92093, USA.
Morgan
M
O'Hayre
Catherina L
CL
Salanga
Tracy M
TM
Handel
Damon J
DJ
Hamel
D000818:Animals; D017277:Drug Approval; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008968:Molecular Conformation; D019707:Receptors, Chemokine / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D054852:Small Molecule Libraries
D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries