ORGANELLE GENOMES OF MALARIAL PARASITES

显然需要有针对性的抗疟疾药物，这些药物的靶点不同于受实地普遍存在耐药性的制剂影响的靶点。由于线粒体在真核生物中发挥的关键作用，它们可以形成这样的靶标。挑战在于找到影响寄生虫线粒体生理学而不影响宿主线粒体的化合物。我们以前确定了疟疾寄生虫的线粒体遗传学和生物化学的几个方面，可能会受到选择性方式的影响。阿托伐醌，一种新开发的广谱抗寄生虫药物，选择性地抑制疟疾线粒体中的电子传递，并被证明可以使寄生虫线粒体内膜的电位崩溃。阿托伐醌作为单一药剂导致不可接受的治疗失败水平，需要包括协同药物氯胍。我们的调查提供了线索，这种协同作用的机制，并为相对缺乏阻力出现的潜在解释。为了继续我们的调查，我们提出了实验，将扩大抗线粒体药物的作用和耐药性的理解，并得出一个更详细的线粒体在疟疾寄生虫的生理学。将使用我们实验室开发的遗传和生化工具来研究药物作用和耐药性的机制。 疟疾基因组计划正在快速接近完成整个恶性疟原虫的DNA序列，并使用这些信息进一步深入了解寄生虫的线粒体生理学，将确定核编码的线粒体基因，并确定其表达模式。为了开发用于研究疟疾寄生虫线粒体生理学的工具，将使用遗传方法来识别将核编码蛋白质引导到疟疾线粒体的信号序列。这些工具将是有价值的疟疾寄生虫的线粒体功能的假设的实验测试。在夏季，提出了一种综合方法，以发展疟疾寄生虫线粒体生理学的机制和功能观点。阿托伐醌的出现为抗寄生虫药物选择性靶向治疗寄生虫提供了新的途径。我们提出的研究将获得更好的药物作用机制的见解，以帮助未来的药物开发策略。拟议的研究还将提供关于寄生虫线粒体功能的基本信息，希望这些信息也能成为开发其他有效疟疾治疗手段的基础。

There is a clear need to have available anti-malarial drugs with targets different from those affected by agents for which resistance is widespread in the field. Because of the critical role played by mitochondria in eukaryotic organisms, they could form such targets. The challenge is to find compounds that affect the parasite mitochondrial physiology without affecting the host mitochondria. We previously identified several aspects of mitochondrial genetics and biochemistry of malaria parasites that could potentially be affected in a selective manner. Atovaquone, a newly developed broad-spectrum anti-parasite drug, selectively inhibits electron transport in malarial mitochondria, and was shown to collapse electropotential across the inner mitochondrial membrane in the parasites. Atovaquone as a single agent leads to unacceptable level of treatment failure, requiring the inclusion of synergistic drug, proguanil. Our investigations have provided clues as to the mechanism for this synergy, and a potential explanation for the relative lack of resistance emergence. To continue our investigations, we propose experiments that will extend the understanding of anti-mitochondrial drug action and resistance, and derive a more detailed view of mitochondrial physiology in malaria parasites. Mechanisms of drug action and resistance will be investigated by using genetic and biochemical tools that have been developed in our laboratory. The Malaria Genome Project is fast approaching completion of the entire DNA sequence of Plasmodium falciparum, and to use this information for further insights into mitochondrial physiology of the parasites, nuclearly encoded mitochondrial genes will be identified and their expression patterns will be determined. To develop tools for studying mitochondrial physiology in malaria parasites, genetic approaches will be used to identify signal sequences that direct nuclearly encoded proteins to the malarial mitochondria. These tools will be valuable for experimental testing of hypotheses regarding mitochondrial functions in malaria parasites. In summer, an integrated approach is proposed to develop a mechanistic and functional view of mitochondrial physiology of malaria parasites.. The approach of selective targeting parasite mitochondrion by anti-parasitic drugs has been established by the advent of atovaquone. Our proposed studies will derive better mechanistic insights into drug action to help future drug development strategies. The studies proposed will also provide basic information on parasite mitochondrial functions with a hope that these too can form the basis from which other effective means for malaria treatment can be developed.