Thymocyte Drug Target of Immune Reconstitution

描述（由申请人提供）：本提案的长期目标是开发第一类小分子口服生物可利用药物，增加胸腺T细胞的产生，增强艾滋病和其他免疫缺陷患者的免疫重建。目前约有4 000万人感染了艾滋病毒。艾滋病毒联合抗病毒疗法（例如HAART）通过将血液中的病毒水平抑制到可检测水平以下，彻底改变了艾滋病的治疗方法。尽管机会性感染的控制得到了极大的改善，但如果停止抗病毒治疗，艾滋病毒通常会恢复到治疗前的水平。事实证明，在HAART治疗后增强对艾滋病毒的免疫控制是难以捉摸的，除非患者很快就能改变感染。来自胸腺的新T细胞的产生被认为有助于HAART期间的免疫重建。治疗性刺激胸腺T细胞（或胸腺细胞）的产生将增加免疫多样性，并填补艾滋病毒感染造成的阻止其控制的空白。更好的免疫重建可以减少对抗病毒治疗的需求，以及随之而来的长期副作用，并大大提高治疗性艾滋病毒疫苗有效的机会。孤儿核受体RORgamma专门控制主要胸腺细胞类型DP胸腺细胞的产生和存活，DP胸腺细胞参与新T细胞受体的产生和选择。RORgamma的激动剂预计可显著提高DP胸腺细胞存活率，并在长期内增加免疫多样性。核受体历来是小分子药物发现的成功靶点，但RORgamma的配体尚未确定。第一阶段的工作建议：(1)优化和建立RORgamma的功能重叠检测，以发现真实的配体，同时拒绝假阳性；(2)在通过合作和购买获得的重点小分子文库中识别潜在的配体；(3)在胸腺细胞功能的细胞基础实验中证实其活性。第一阶段为第二阶段进一步筛选和定向合成RORgamma的特异性高亲和力配体奠定基础，用于临床前原理验证研究。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to develop the first class of small molecule, orally-bioavailable drugs that increases T cell production from the thymus and enhances immune reconstitution in AIDS and other immunodeficiencies. About 40 million individuals are currently infected with HIV. Combined antiviral therapies for HIV (e.g. HAART) have revolutionized the treatment of AIDS by suppressing blood levels of virus to below detectable levels. Even though control of opportunistic infections is greatly improved, HIV generally retums to pretreatment levels if antiviral therapy is stopped. Enhanced immune control of HIV following HAART has proved elusive except for patients treated very soon alter infection. New T cell production from the thymus is believed to contribute to immune reconstitution during HAART. Therapeutic stimulation of thymic T cell (or thymocyte) production will increase immune diversity and fill gaps created by HIV infection that prevent its control. Better immune reconstitution could reduce the requirement for antiviral therapy, with its attendant long-term side effects, and greatly improve the chances that a therapeutic vaccine for HIV can be effective. The orphan nuclear receptor RORgamma specifically controls the production and survival of the major thymocyte cell type, the DP thymocyte, that is involved in creation and selection of new T cell receptors. An agonist to RORgamma is predicted to markedly enhance DP thymocyte survival, and, over the long term, to increase immune diversity. Nuclear receptors have historically been successful targets for small molecule drug discovery, but ligands have yet to be identified for RORgamma. This Phase 1 effort proposes to (1) optimize and establish functionally-overlapping assays for RORgamma to enable discovery of authentic ligands while rejecting false positives; (2) identify potential ligands in focused small molecule libraries obtained through partnership and purchase; and (3) confirm activity in cell-based assays of thymocyte function. Phase 1 lays the foundation for further screening and directed synthesis of specific, high affinity ligands to RORgamma in Phase 2 for pre-clinical proof-of-principle studies.