Generation of multi-functional biological probes based on the anti-inflammatory Tanshinones

我们假设，确定TIIA的分子靶点将有助于开发新的炎症性疾病的促消退疗法，这可能比目前的治疗方法更有效。此外，丹参酮可用于触发细胞凋亡诱导的吞噬细菌的杀伤，使其成为潜在的宿主靶向抗感染剂。我们最近开发了一个强大的合成化学程序的克级制备一系列丹参酮，使用合成化学方法，以调查所需的生物活性的关键功能。从这一点上，我们已经开发了一个更好的理解的化学设计标准，开发合成丹参酮，可以纳入探针，调查生物功能。我们将使用这些来制备化学修饰的“多功能”丹参酮类似物，这样我们就可以用荧光团或生物素结合剂或光亲和探针，或这些的组合进行标记。这套探针将使我们能够使用互补和最先进的成像技术更详细地研究这些分子的作用机制。它还将提供一个手柄，使我们能够从中性粒细胞中提取丹参酮的生物靶点，并通过质谱法对其进行鉴定。这将为丹参酮的作用模式提供证据，并允许设计更有效的治疗剂。这些生物探针的化学合成具有显著的新奇，而所得的生物靶标将具有显著的长期重要性。

We hypothesise that identifying the molecular target of TIIA will facilitate the development of novel pro-resolution therapeutics for inflammatory disease, which may be more effective than current treatments. In addition, Tanshinones may be useful to trigger apoptosis induced killing of phagocytosed bacteria, making them a potential host-targeted anti-infective agent. We have recently developed a robust synthetic chemical procedure for the gram-scale preparation of a series of Tanshinones, using synthetic chemistry approaches in order to investigate the key functionalities that are required for biological activity. From this we have developed a better understanding of the chemistry design criteria for developing synthetic tanshinones that can incorporate probes to investigate biological function. We will use these to prepare chemically modified 'multi-functional' Tanshinone analogues such that we can label with fluorophores or biotin binders or photoaffinity probes, or a combination of these. This suite of probes will give us the ability to study mechanisms of action of these molecules in more detail using complementary and state of the art imaging technologies. It will also provide a handle to allow us to pull down the biological targets of Tanshinones from neutrophils and identify them by mass spectrometry. This will provide evidence for the mode of action of tanshinones and allow the design of more potent therapeutic agents. The chemical synthesis of these biological probes has significant novelty, while the resulting biological targets will have significant longer term importance.