Small Molecular Screen for Thymocyte Drug Target (RMI)

描述（由申请人提供）：免疫调节是药物发现研究的主要目标，对感染性疾病、免疫缺陷和自身免疫性疾病有影响。 一种小分子药物靶点已经在胸腺中部分表征，预测其通过逆转免疫多样性的病理性丧失来增强AIDS和其他免疫缺陷中免疫系统的重建。 质量改善的免疫重建是艾滋病-超越联合逆转录病毒治疗或HAART期间发生的-将是至关重要的，以减少对目前的抗病毒治疗的依赖，伴随着严重的副作用，并实施艾滋病毒的治疗性疫苗。 目标靶点被指定为“孤儿”受体，因为选择性和/或有效配体未知，因此其药理学尚未研究。 该提案的目的是开发针对该靶标的高通量筛选（HTS）测定，以能够筛选大型（> 50，000）化合物文库。 我们将使用HTS来确定一系列化合物作为潜在的线索，选择其中最好的来设计更有效的化合物，用于阐明受体功能和药物开发。 我们已经确定了一些合成的小分子配体作为阳性对照HTS开发在一个初始的，小规模的屏幕。 该提案的目标是（i）开发用于鉴定激动剂和拮抗剂的测定条件，以及（ii）将测定按比例缩小至384孔板格式，以便在HTS环境中实施。

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.