Small Molecular Screen for Thymocyte Drug Target (RMI)

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DESCRIPTION (provided by applicant): The regulation of immunity is a major goal of drug discovery research, with impacts on infectious disease, immunodeficiency, and autoimmune disease. A small molecule drug target has been partially characterized in the thymus that is predicted to enhance reconstitution of the immune system in AIDS and other immunodeficiencies by reversing the pathological loss of immunological diversity. Qualitatively improved immune reconstitution is AIDS-beyond what takes place during combined retroviral therapy or HAART-will be essential to reduce reliance on current antiviral therapies, with their attendant serious side effects, and to implement a therapeutic vaccine for HIV. The target of interest is designated as an "orphan" receptor because selective and/or potent ligands are not known and consequently its pharmacology has not been investigated. The objective of this proposal is to develop a high-throughput screening (HTS) assay for this target to enable screening of large (>50,000) compound libraries. We will use HTS to identify a range of compounds as potential leads, selecting the best of these to design more potent compounds for elucidation of receptor function and drug development. We have identified a few synthetic small molecule ligands as positive controls for HTS development in an initial, small-scale screen. The goals of the proposal are (i) to develop assay conditions for identifying both agonists and antagonists and (ii) to scale down the assay to a 384-well plate format for implementation in an HTS environment.