Illudine, a novel potent trypanocidal natural product; optimisation of simplified analogues, investigating its mode of action and elucidation of its p

Illudine，一种新型强效杀锥虫天然产物；

• 批准号: 2745660
• 金额: --
• 依托单位: University of St Andrews
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2745660
• 关键词: Illudine; novel; potent; trypanocidal; natural

The parasitic protozoa Trypanosoma brucei, Trypanosoma cruzi, and Leishmania speciesare the causative agents of the "neglected" tropical diseases: African sleeping sickness,Chagas' disease and leishmaniasis. Collectively, these diseases affect millions of peopleand represent a huge percentage of the world's communicable disease burden. Currentdrug treatments are woefully inadequate, having problems of toxicity, difficult administration in the field, cost and emerging resistance. There is an urgent need for identification of novel therapeutic targets, allowing development of lead compounds into safe, cheap, and easy to administer drugs if these diseases are to be eradicated/controlled; a WHO priority by 2020.Natural products arise from the evolution of organisms to produce secondary metabolites, which enhance the survival and competitiveness of the organism in its habitat. These chemical entities are often complex, structurally diverse, and already biologically validated by their very nature making them ideal starting points for drug candidates. Historically, natural products have proved to be a bountiful resource of lead compounds in drug discovery, with almost 50% of all approved drugs between 1981 and 2011 being natural products themselves or derivatives thereof. Natural products and natural product-like scaffolds, and the typical complexity and diversity that accompanies them, are vastly underrepresented in synthetic libraries, mainly due to their challenging synthesis and enormous difficulty of structural modifications. It has, however, been shown that there is significant positive correlation of greater complexity and incorporation of stereogenic centres, with the transitioning of compounds from discovery, through clinical trials and eventually to drugs. Utilising the inspiration of natural products, for their structural and functional diversity, and biological validation is a beneficial approach for increasing probability of both biological activity and availability.The Smith group have previously undertaken a screen of NIH Natural Products Collection (120isolated compounds) against all three parasites and came up with several highly potent compounds with EC50 in the low nM range with high selectivity versus mammalian cells.One of these targets was Fumagillin, which has been the subject of research in the Florence and Smith groups to optimize the SAR of simplified targets and identify its protein target(s) in T. brucei.Another potent natural product identified in this screen is Illudine M, a sequiterpene with an Ec50 against T. cruzi of 6.67 nM. The synthesis of which has been studied, along with several natural variants. https://pubs.acs.org/doi/pdf/10.1021/acs.joc.0c01301This will be the main topic of this studentship to undertake the synthesis of illudine and some simplified analogues allowing subsequent testing against the parasites to obtain some SAR and initial phenotyping. Suitable moieties will be added to the optimized simplified analogues allowing cross-linking and affinity purifications to identify protein targets.If time allows and as a backup several other potent trypanocidal natural product hits will investigated including several cyclopeptide analogues.

寄生性原生动物布氏锥虫、克氏锥虫和利什曼原虫是“被忽视的”热带疾病的病原体：非洲昏睡病、恰加斯病和利什曼病。总的来说，这些疾病影响着数百万人，占世界传染病负担的很大比例。目前的药物治疗严重不足，存在毒性、难以现场管理、成本和新出现的耐药性等问题。如果要根除/控制这些疾病，迫切需要确定新的治疗靶点，从而将先导化合物开发成安全、廉价和易于给药的药物;这是世卫组织到2020年的优先事项。天然产物来自生物体的进化，产生次级代谢产物，增强生物体在其栖息地的生存和竞争力。这些化学实体通常是复杂的，结构多样的，并且已经通过其性质进行了生物学验证，使其成为候选药物的理想起点。从历史上看，天然产物已被证明是药物发现中先导化合物的邦蒂富尔资源，1981年至2011年期间所有批准的药物中几乎50%是天然产物本身或其衍生物。天然产物和天然产物样支架，以及伴随它们的典型复杂性和多样性，在合成文库中的代表性大大不足，主要是由于它们具有挑战性的合成和结构修饰的巨大困难。然而，已经表明，更大的复杂性和立体中心的并入与化合物从发现、通过临床试验并最终到药物的转变存在显著的正相关。利用天然产品的灵感，因为它们的结构和功能多样性，生物学验证是提高生物活性和可用性的一种有益方法。Smith小组以前曾对NIH天然产物保藏中心进行过筛选，（120个分离化合物）针对所有三种寄生虫，并提出了几种高效化合物，其EC 50在低nM范围内，对哺乳动物细胞具有高选择性。其中一种靶标是烟曲霉素，其已经成为佛罗伦萨和史密斯小组的研究主题，以优化简化靶标的SAR并鉴定其在T.在该筛选中鉴定的另一种有效的天然产物是Illudine M，其是一种具有针对T. cruzi为6.67 nM。它的合成已经被研究过了，沿着还有几种天然的变体。https://pubs.acs.org/doi/pdf/10.1021/acs.joc.0c01301This将是这个学生奖学金的主要主题，以进行伊鲁定和一些简化的类似物的合成，允许随后对寄生虫进行测试，以获得一些SAR和初始表型。合适的部分将被添加到优化的简化的类似物，允许交联和亲和纯化，以确定蛋白质targets.If时间允许，并作为备份几个其他有效的杀锥虫天然产物命中将调查，包括几个环肽类似物。