Validating IPCS as an antileishmanial drug target

利什曼病是由原生动物利什曼原虫属引起的昆虫媒介传播。使全球超过3.5亿人处于危险之中。目前有1 200多万人受到感染，造成了经济负担，最突出的特点是这种疾病造成200万丹麦人死亡。目前治疗利什曼病是困难的，需要长期的，昂贵的药物治疗过程中使用旧的药物与不良的安全性指标，需要密切的医疗监督。此外，对当前反利什曼主义者的抵制越来越明显。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，这强调了对靶向新作用模式的新药的重大需求。在最近的工作中，我们已经确定了一种酶，IPCS，从利什曼原虫没有直接的哺乳动物等效物。在使用这种酶开发生物化学和基于细胞的测定之后，我们已经筛选了GSK收集的1.8M化合物的潜在抑制剂。经过二次筛选，我们已经确定了5种化合物具有良好的活性和选择性水平的利什曼酶，也有合适的理化概况（Lipinski规则），以探索作为新的药物的线索。在这个为期四年的博士项目中，我们将验证IPCS作为化学和遗传药物的目标。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，并将支持随后的努力，将这些命中发展为未来PPP资助的药物发现计划的线索。因此，该项目将有助于实现全球健康的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的培训，它解决了RCUK为代表下一代生物医学科学领导者的训练有素的多学科科学家强调的关键技能短缺。

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.