Characteristics of chloroquine translocation by pfCRT

pfCRT 氯喹易位的特点

• 批准号: G0801896/1
• 负责人: Marcus Allen
• 金额: $ 43.31万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0801896%2F1
• 关键词: Characteristics; chloroquine; translocation; pfCRT

Malaria continues its reign as one of the largest causes of death in the developing world. Currently, the main therapeutic strategy is drug administration, or chemotherapy. The drug chloroquine is one of the most widely used anti-malarial agents. Chloroquine enters the malarial parasite whilst it resides in red blood cells (erythrocytes). During this period the parasite grows by virtue of digesting the protein rich erythrocyte environment. This digestion occurs within a specific compartment of the parasite, known as the food vacuole. Chloroquine also enters the food vacuole and inhibits a specific pathway involved in digestion of erythrocyte proteins. In turn, this causes a build up of toxic by-products and ultimately leads to death of the parasite. Unfortunately, in many regions worldwide, the malaria parasites have built up a resistance to chloroquine, and many other anti-malarial drugs. There are numerous pathways contributing to resistance in malaria, but the main one associated with chloroquine resistance is caused by mutations in the PfCRT gene. The PfCRT gene produces a protein that resides on the surface of the food vacuole and is thought to confer resistance by altering the amount of chloroquine accumulating in this compartment. It is unclear what this protein does normally in the parasite and what consequences the mutations have on its activity.Our primary aim is to determine how the PfCRT protein contributes to resistance against chloroquine and whether its actions can be overcome.To enable us to reach this objective, we have developed a novel experimental system to directly examine PfCRT activity in isolation. The system will enable us to examine the following key issues:(i) Providing information on which anti-malarial drugs (other than chloroquine) are targeted by PfCRT and therefore succumb to resistance.(ii) Catalogue compounds capable of inhibiting PfCRT, which could potentially restore chloroquine accumulation and overcome resistance. Positive compounds could be used in future chemical programs to develop more potent agents.(iii) Determine whether PfCRT pumps drugs in an energy dependent manner or by simply acting as a pore through which chloroquine can exit the food vacuole.Providing a greater understanding of how PfCRT causes resistance to chloroquine in malaria will significantly enhance future strategies to overcome its unwanted activity and thereby circumvent the resistance to chemotherapy.

疟疾仍然是发展中世界最大的死亡原因之一。目前，主要的治疗策略是给药或化疗。氯喹是最广泛使用的抗疟疾药物之一。氯喹进入疟疾寄生虫，而它驻留在红细胞（红细胞）。在此期间，寄生虫通过消化富含蛋白质的红细胞环境而生长。这种消化发生在寄生虫的特定隔室中，称为食物泡。氯喹也进入食物泡，抑制红细胞蛋白质消化的特定途径。反过来，这会导致有毒副产品的积累，最终导致寄生虫死亡。不幸的是，在世界上许多地区，疟原虫已经对氯喹和许多其他抗疟疾药物产生了抗药性。有许多途径有助于疟疾的耐药性，但与氯喹耐药性相关的主要途径是由PfCRT基因突变引起的。PfCRT基因产生一种位于食物泡表面的蛋白质，并被认为通过改变在该隔室中积累的氯喹的量来赋予抗性。目前还不清楚这种蛋白在寄生虫中的正常作用以及突变对其活性的影响，我们的主要目的是确定PfCRT蛋白如何有助于对氯喹的抗性以及是否可以克服其作用，为了使我们能够达到这一目标，我们开发了一种新的实验系统来直接检测PfCRT活性。该系统将使我们能够研究以下主要问题：（i）提供资料，说明哪些抗疟疾药物（氯喹除外）是PfCRT的目标药物，因此会产生抗药性。(ii)目录化合物能够抑制PfCRT，这可能会恢复氯喹积累和克服阻力。阳性化合物可用于未来的化学项目，以开发更有效的药物。(iii)确定PfCRT泵的药物是否在能量依赖的方式或通过简单地充当一个孔，通过它氯喹可以退出food vacuole.Providing一个更好的理解PfCRT如何导致耐药性氯喹疟疾将显着提高未来的战略，以克服其不必要的活动，从而规避化疗的耐药性。