Validating IPCS as an antileishmanial drug target

利什曼病是由原生动物利什曼原虫引起的一种病媒昆虫传播的疾病。这将全球超过3.5亿人置于危险之中。目前有超过1200万人受到感染，造成的经济负担最突出的是该疾病造成的200万死亡寿命年。目前利什曼病的治疗很困难，需要使用安全适应症较差的旧药进行漫长而昂贵的药物治疗，需要密切的医疗监督。此外，对当前抗利什曼症药物的抵触情绪日益明显。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。总体而言，这强调了针对新的行动模式的新药物的重大需求。在最近的工作中，我们从利什曼原虫中鉴定出一种酶，IPCS，它在哺乳动物中没有直接的等价物。在使用这种酶开发生化和基于细胞的分析后，我们已经从GSK收集的1.8M化合物中筛选出潜在的抑制剂。经过二次筛选，我们确定了5个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(利平斯基规则)，可以作为新药的先导化合物。在这个为期四年的博士项目中，我们将从化学和遗传两个方面验证IPCS作为药物靶标的有效性。与MRCT的合作将为该项目带来必要的行业专业知识、培训和设施，包括基于硅胶和实验室的药物化学和PK/PD研究，并将支持后续的努力，将这些HITS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卫生领域的MRC战略，使人们能够健康长寿。此外，它还符合MRC支持科学家的战略目标。它结合了药物化学、合成化合物筛选、蛋白质特性、分子生物学和寄生虫学方面的培训，解决了RCUK强调的代表下一代生物医学科学领袖的训练有素的多学科科学家的关键技能短缺问题。

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.