Developing synergisers of the antimalarial drug, chloroquine, for the treatment of chloroquine-resistant P. falciparum.

疟疾是一种使人衰弱的寄生虫病，每年造成大约200万儿童死亡。由于寄生虫耐药性的发展，氯喹等药物变得越来越无用，因此迫切需要了解现有抗疟药的作用方式和耐药性的分子基础，并设计出可负担得起的替代氯喹的治疗方法。众所周知，一些本身抗疟活性很差的化合物可以协同氯喹的作用。这可能涉及抑制蛋白质的活性，这些蛋白质直接或间接地将氯喹从寄生虫消化器官的作用部位挤出来。不幸的是，迄今为止研究的氯喹增效剂毒性太大，无法在体内使用。在初步研究中，我们已经确定了一些适合用于疟疾患者的化合物，包括一种广泛使用的抗疟疾药物伯氨喹，它可以协同氯喹的活性，对抗氯喹耐药寄生虫。我们将试图了解这种相互作用的分子基础。这将使我们能够确定用于治疗疟疾的氯喹和一种逆转耐药性的喹啉的最佳组合。这可能会延长这种重要的抗疟疾药物的临床寿命。获得的信息也可能有助于设计新的抗疟疾药物。

Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of and the molecular basis of resistance to existing antimalarials and to design affordable treatments that can replace chloroquine. It is known that some compounds, that have only poor antimalarial activity themselves, can synergise the action of chloroquine. This may involve the inhibition of the activity of proteins that directly or indirectly extrude chloroquine from its site of action in the parasite's digestive apparatus. Unfortunately, thechloroquine synergisers examined to date have been too toxic to be useful in vivo. In preliminary studies we have identified some compounds that would be suitable for use in malaria patients, including a widely used antimalarial drug, primaquine, that can synergise the activity of chloroquine against chloroquine-resistant parasites. We will attempt to understand the molecular basis of this interaction. This will allow us to define optimal combinations of chloroquine and a resistance-reversing quinoline for use treating malaria. This could extend the clinical life of this important antimalarial drug. The information obtained may also help to design novel antimalarial drugs.