Bio-Inspired Glycan Based Probes for Rapid Detection of TB Infection

2020年共有150万人死于结核病，这是全球第13大最常见的死亡原因，也是仅次于COVID-19.1的第二大传染病死亡原因。大多数结核病感染是无症状的，需要确定潜在或新生感染，以防止传播并迅速开始适当治疗。我们的目标是与FluoretiQ有限公司合作，开发一种新的快速诊断工具来帮助这一努力。结核分枝杆菌(Mtb)已被证明与多种糖链相互作用，包括在Mtb细胞膜中发现的非哺乳动物二糖海藻糖。2，3我们建议利用这些相互作用来设计和合成各种由海藻糖或海藻糖类似物连接到纳米材料传感器上的探针，目的是实现与Mtb的选择性结合，从而最终检测Mtb。海藻糖由两个α，α(1-1‘)连接的葡萄糖单元组成，以前在Galan基团中的工作已经实现了Au(III)催化保护的2-脱氧吡喃糖半缩醛到2，2’-二脱氧海藻糖类似物的偶联。4我们的目标是将这一方法扩展到接受全氧底物，以便以收敛的方式获得各种官能化的海藻糖类似物。我们希望应用自动化合成来通过实验设计的方法来精炼产量，并随后合成具有适当功能的海藻糖类似物库，以连接到纳米平台。该文库将包括混合海藻糖(例如半乳糖-葡萄糖和甘露糖-葡萄糖)。然后，将与细胞和分子医学院的同事合作，对这些细胞与分枝杆菌的结合进行筛选。

A total of 1.5 million people died from tuberculosis disease in 2020, it is the 13th most frequent cause of death worldwide, and the second largest cause of death by infectious disease behind COVID-19.1 The majority of TB infections are asymptomatic and there is a need to identify latent or nascent infections to prevent transmission and start appropriate treatment quickly. Our goal is to work in collaboration with FluoretiQ Ltd. to develop a new rapid diagnostic tool to aid in this endeavour. Mycobacterium tuberculosis (Mtb) has been shown to interact with a variety of glycans, including the non-mammalian disaccharide trehalose, found in the Mtb cell envelope.2,3 We propose to leverage these interactions in the design and synthesis of a variety of probes consisting of trehalose or analogues of trehalose conjugated to nanomaterial-based sensors, with the aim of achieving selective binding to, and therefore definitive detection of Mtb. Trehalose consists of two alpha,alpha (1-1') linked glucose units, and previous work in the Galan group has achieved the Au(III) catalysed coupling of protected 2-deoxy pyranose hemiacetals into 2,2'-dideoxy trehalose analogues.4 We aim to expand this methodology to accept fully oxygenated substrates in order to access a variety of functionalised trehalose analogues in a convergent fashion. We would like to apply automated synthesis to refine yields with a design of experiments approach, and subsequently synthesise a library of trehalose analogues, with appropriate functionality for conjugation to nano-platforms. This library will include mixed trehaloses (e.g. galactose-glucose and mannose-glucose). These will then be screened for binding to mycobacteria in collaboration with co-workers in the School of Cellular and Molecular Medicine.