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，其增加胸腺T细胞的产生并增强艾滋病和其他免疫缺陷的免疫重建。目前约有4 000万人感染艾滋病毒。HIV的联合抗病毒疗法（例如HAART）通过将病毒的血液水平抑制到低于可检测水平而彻底改变了艾滋病的治疗。尽管机会性感染的控制得到了很大改善，但如果停止抗病毒治疗，HIV通常会恢复到治疗前的水平。HAART后增强对HIV的免疫控制已被证明是难以捉摸的，除非患者在感染后很快接受治疗。新的T细胞从胸腺产生被认为有助于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空白，防止其控制。更好的免疫重建可以减少抗病毒治疗的需要，以及随之而来的长期副作用，并大大提高艾滋病毒治疗性疫苗有效的机会。孤儿核受体ROR γ特异性控制主要胸腺细胞类型DP胸腺细胞的产生和存活，其参与新T细胞受体的产生和选择。预计ROR γ的激动剂可显著增强DP胸腺细胞存活，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ROR γ的配体尚未鉴定。该第1阶段工作提出：（1）优化和建立ROR γ的功能重叠测定，以发现真实配体，同时排除假阳性;（2）在通过合作和购买获得的集中小分子文库中鉴定潜在配体;（3）在基于细胞的胸腺细胞功能测定中确认活性。第1阶段为第2阶段进一步筛选和定向合成ROR γ的特异性高亲和力配体奠定了基础，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.