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

拟议的研究将解决有关cd1限制性iNKT细胞结构活性关系影响的基本问题，以及我们如何利用其免疫刺激和免疫调节特性来帮助治疗许多临床疾病。通过使用知情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化合物家族的多种免疫调节特性作为潜在的免疫治疗药物。iNKT ncell ?配体，如α - galcer相关类似物和其他新型合成激动剂，在三个治疗领域具有潜在的用途。首先，基于α - galcer的药物的Th1细胞因子诱导特性可以作为短期免疫刺激增强，提供针对多种病原体的保护。其次，这些化合物的非特异性免疫激活特性可能被用作疫苗免疫佐剂，以增强对各种肿瘤和传染病的细胞毒性反应。第三，iNKT细胞激动剂的Th2细胞因子诱导特性可能被证明在控制自身侵袭性免疫反应方面是有效的。关键的挑战仍然是如何通过使用特定的激动剂来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的复杂结构的iNKT激动剂并不特别适合临床开发，因此迫切需要开发新的更简单的化合物，能够诱导靶向人iNKT细胞反应。这将通过一个知情的结构设计过程来实现。此外，我们打算通过对亲本iNKT细胞激动剂α - galcer进行结构修饰，以创造新的类似物，从而最大限度地提高我们成功的机会，基于我们之前获得的结构活性关系(SAR！S)影响/支配它们的生物学结果。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翻译。在这个应用程序中，我们的理念是提供一个多学科，最先进的研究计划，以实现这些目标。提出的方法是新颖的，包括：化学合成，硅设计，人体体外筛选测定和新颖的体内验证模型。

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.