Design, synthesis, and assessment of specific iNKT cell agonists for clinical applications

拟议的研究将解决有关CD 1d限制性iNKT细胞的结构活性关系的影响的基本问题，以及我们如何利用它们的免疫刺激和免疫调节特性来帮助治疗一些临床疾病。通过使用知情的设计方法来产生新的iNKT细胞激动剂，我们希望开发一种更合理的策略来利用该家族化合物作为潜在的免疫调节药物的多种免疫调节特性。iNKT？ncell？N配体如α-GalCer相关类似物和其它新型合成激动剂在三个治疗领域具有潜在用途。首先，基于α-GalCer的药剂的Th 1细胞因子诱导特性可以提供针对多种病原体的保护，作为短期免疫刺激增强。第二，这些化合物的非特异性免疫激活特性可用作疫苗免疫佐剂以增强对各种瘤形成和感染性疾病的细胞毒性应答，第三，iNKT细胞激动剂的Th 2细胞因子诱导特性可证明在控制自身攻击性免疫应答方面有效。关键的挑战仍然是如何通过使用特异性激动剂选择性地激活和操纵iNKT细胞的不同功能，然后将其转化为临床应用。由于目前基于α-GalCer的iNKT激动剂的复杂结构不是特别适合于临床开发，因此迫切需要开发能够诱导靶向人iNKT细胞应答的新的更简单的化合物。这将通过一个知情的结构设计过程来实现。此外，我们打算通过对母体iNKT细胞激动剂α-GalCer进行结构修饰来最大限度地提高成功的机会，以根据我们先前获得的结构活性关系（SAR！影响/支配其生物学结果。我们还将使用更复杂的人类体外筛选试验来改善新激动剂的临床转化。在这个应用程序中，我们的理念是提供一个多学科的，最先进的研究计划，以解决这些目标。所提出的方法是新颖的，包括：化学合成，在硅片设计，人类在体外筛选试验和新的体内验证模型。

The proposed research will address fundamental questions about the influence of the structural activity relationship of CD1d-restricted iNKT cells and how we may take advantage of both their immunostimulatory and immunoregulatory properties to help treat a number of clinical conditions. By using an informed design approach to generating new iNKT cell agonists, we hope to develop a more rational strategy to exploit the diverse immunomodulatory properties of this family of compounds as potential immunotherapeutic drugs. iNKT?ncell?nligands such as alpha-GalCer associated analogues, and other novel synthetic agonists, have potential use in three therapeutic areas. First, the Th1 cytokine-inducing properties of alpha-GalCer-based agents could provide protection against a variety of pathogens as a short-term immunostimulatory boost. Second, the non-specific immune activation properties of these compounds may be exploited as vaccine immunoadjuvants to boost cytotoxic responses to various neoplasias and infectious diseases, and third, the Th2 cytokine-inducing properties of iNKT cell agonists may prove effective at controlling auto-aggressive immune responses. The key challenge remains how to activate and manipulate the different functions of iNKT cells selectively, through the use of specific agonists, which can then be translated into clinical applications. As the complex structures of current iNKT agonists based on alpha-GalCer are not particularly suitable for clinical development, there is an urgent need to develop new simpler compounds that are capable of inducing targeted human iNKT cell responses. This will be achieved by a process of informed, structural design. In addition we intend to maximise our chances of success by making structural modifications to the parent iNKT cell agonist, alpha-GalCer, to create new analogues, based on our previously acquired knowledge of the structural activity relationships (SAR!s) that influence/govern their biological outcome. We will also use more sophisticated human in vitro screening assays to improve clinical translation of new agonists. In this application, our philosophy is to deliver a multidisciplinary, state-of-the-art programme of studies in order to address these goals. The proposed methodologies are novel and include: chemical synthesis, in silico design, human in vitro screening assays and novel in vivo verification models.