Small Molecule Antagonists of Chemokine Receptors - is Promiscuity a Virtue?

Abstract

A major function of the chemokine system is to coordinate the recruitment of leukocytes to specific locations within the tissues. The involvement of chemokine receptors in a multitude of inflammatory diseases, coupled with their belonging to the highly "druggable" GPCR superfamily, makes them excellent candidates for the development of novel drugs by the pharmaceutical industry. Despite descriptions in the literature of many specific small molecule chemokine receptor antagonists, none have yet shown efficacy in the clinical inflammatory setting. In this article, we discuss the successes and failures of chemokine receptor antagonists in the clinic and review a subset of molecules that are documented as having activity at two or more chemokine receptors. It may be that a more permissive approach, targeting several chemokine receptors with a single molecule will provide the next generation of anti-inflammatory drugs.

Remodeling our concept of chemokine receptor function: From monomers to oligomers

“…15 Apparently, there is considerable promiscuity between chemokines and their receptors, with various ligands that can associate the same receptor and distinct receptors that can bind the same ligand. 16 Emerging evidence nonetheless indicates some differences in the signaling cascades and functions triggered by ligands that bind the same receptor, [17][18][19] suggesting that the promiscuity concept should be revised, if not simply discarded. In addition to promiscuity, the stage of CKR at the cell surface has been intensively studied in the last years.…”

Evasins: Tick Salivary Proteins that Inhibit Mammalian Chemokines

“…The discovery of numerous Evasins with differing chemokine-binding selectivity, and their systemic antichemokine effects following parenteral administration, indicate that Evasins could be of therapeutic use in the treatment of chemokine-associated inflammatory diseases. To date, therapeutic intervention through blockade of chemokine activity by several different approaches has not been particularly successful [53,54]. This lack of success has often been attributed to the promiscuity of the system, in that several chemokines need to be neutralized to be efficacious in inflammation.…”

Agarose Spot as a Comparative Method for in situ Analysis of Simultaneous Chemotactic Responses to Multiple Chemokines

“…Therefore, there are now a number of examples where antagonism of more than one chemokine receptor is considered advantageous as a treatment strategy 44–47 . For example, there is some clinical evidence to support the hypothesis that the CXCR4 and CCR7 axes may work in tandem to promote the dissemination of cancer.…”