Validating IPCS as an antileishmanial drug target

验证 IPCS 作为抗利什曼病药物靶点

• 批准号: 1930892
• 金额: --
• 依托单位: Durham University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1930892
• 关键词: Validating; IPCS; antileishmanial; drug; target

Leishmaniasis is an insect vector-borne caused by the protozoan Leishmania spp. that places over 350 million people world-wide at risk. There are greater than 12 million people currently infected resulting in an economic burden that is best characterised by the 2 million DALYs caused by the disease. Current treatment of leishmaniasis is difficult requiring a long, costly course of drug treatment using old drugs with poor safety indications requiring close medical supervision. Moreover, resistance to current antileishmanials is increasingly evident. As such the WHO ranks leishmaniasis as one of the world's most neglected diseases. Collectively this emphasises a major need for new drugs targeting new modes of actions. In recent work we have identified an enzyme, IPCS, from Leishmania that has no direct mammalian equivalent. Having used this enzyme to develop biochemical and cell based assays, we have screened the GSK collection of 1.8M compound for potential inhibitors. Following secondary screening, we have identified 5 compounds with good levels of activity and selectivity for the leishmanial enzyme that also have suitable physicochemical profiles (Lipinski rules) to be explored as leads for new drugs. In this four year PhD project, we will validate IPCS as the drug target both chemically and genetically. The collaboration with MRCT will bring essential industrial expertise, training and facilities, for in silico and lab based medicinal chemistry and PK/PD studies, to the project and will also underpin subsequent efforts to develop these hits into leads for a future PPP funded drug discovery programme. As such this project will help deliver the MRC strategy in Global Health, enabling people to Live a long and Health Life. Moreover, it also meets the MRC strategic aim of Supporting Scientists. Combining training in medicinal chemistry, synthesis compound screening, protein characterisation, molecular biology and parasitology it addresses the crucial skills shortage highlighted by RCUK for highly trained multidisciplinary scientists who represent the next generation of biomedical scientific leaders.

利什曼病是一种由原生动物利什曼原虫引起的虫媒传播疾病，全世界有超过3.5亿人处于危险之中。目前有1 200多万人受到感染，造成经济负担，最显著的特征是该病造成200万残疾调整生命年。目前治疗利什曼病很困难，需要使用安全性差、需要密切医疗监督的旧药物进行长期、昂贵的药物治疗。此外，对当前反利什曼动物的抵抗也越来越明显。因此，世界卫生组织将利什曼病列为世界上最被忽视的疾病之一。总的来说，这强调了对针对新作用模式的新药的主要需求。在最近的工作中，我们从利什曼原虫中发现了一种酶，IPCS，它在哺乳动物中没有直接的等同物。在使用该酶开发生化和细胞基础分析后，我们筛选了GSK收集的180 m化合物的潜在抑制剂。经过二次筛选，我们确定了5种对利什曼酶具有良好活性和选择性的化合物，这些化合物也具有合适的物理化学特征（Lipinski规则），可以作为新药的先导物。在这个为期四年的博士项目中，我们将从化学和遗传学上验证IPCS作为药物靶点。与MRCT的合作将为该项目带来必要的工业专业知识、培训和设施，用于基于计算机和实验室的药物化学和PK/PD研究，并将支持后续努力，将这些热门药物开发成未来PPP资助的药物发现计划的先导。因此，该项目将有助于在全球卫生领域实施MRC战略，使人们能够过上健康长寿的生活。此外，它也符合MRC支持科学家的战略目标。结合药物化学、合成化合物筛选、蛋白质表征、分子生物学和寄生虫学方面的培训，它解决了RCUK强调的训练有素的多学科科学家的关键技能短缺问题，这些科学家代表了下一代生物医学科学的领导者。