Cell-Based Screening for Multi-Functional Chemokine Receptor Modulators

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DESCRIPTION (provided by applicant): Eight of the ten CC chemokine receptors have been implicated in the pathology of allergy, asthma, and other immunological diseases. Pharmacological inhibition of five separate receptors has been shown to ameliorate disease in a variety of animal models making the CC chemokine receptor family a target-rich class of receptors for asthma and allergic disease. In spite of decades of development and several clinical trials, no drugs targeting chemokine receptors for inflammatory disease have progressed to the public. The current hypothesis is that since the majority of chemokine receptors are activated by multiple ligands and one-third of chemokine ligands activate multiple receptors, this complexity and redundancy may not be efficiently addressed by the one target, one drug screening model. Most endogenous chemokines target multiple receptors and thus achieve specific biological effects through a "selective non-selectivity" whereby a small subset of receptors is activated to varying degrees by a specific ligand. Similarly, many very efficacious drugs are only effective because they modulate multiple targets For complex multi-component diseases such as inflammation and allergic disease where several chemokine receptors have been implicated in disease progression, the path to therapeutic intervention would benefit from being able to screen compounds for their effects across the entire family of targets simultaneously, to isolate drugs with the proper activation or inhibition profiles. The subject of this Phase I SBIR proposal is the development of a cell-based assay system to enable the simultaneous screening of nine disease-relevant chemokine receptors to find novel agonists and antagonists with the desired selectivity profiles. The successful completion of these studies will create a system to characterize the inhibitory profile of a compound over a range of receptors and enable the discovery of therapeutic candidates with novel selectivity properties. PUBLIC HEALTH RELEVANCE: Asthma and allergic diseases involve a complex web of receptors with highly redundant functions making it difficult to achieve therapeutic efficacy using the traditional, one drug one receptor model. The system described here is a method of identifying the effects of novel therapies across a broad range of targets to find unexpected activities of known drugs and enable drug discovery efforts that specifically target multiple receptors.