Towards a Structural Systems Biology Approach for Anti-Trypanosomal Therapeutics

描述（由申请人提供）：锥虫是一组寄生虫，可引起几种毁灭性的热带疾病，包括非洲的非洲昏睡病和中美洲和南美洲的恰加斯病。每年，最贫穷国家有数百万人面临这些疾病的风险并遭受这些疾病的折磨。然而，治疗这些疾病的有效药物严重缺乏。锥虫寄生虫具有独特的生物学过程，其中它们的线粒体rna在翻译之前被广泛编辑。这个过程发生在一个被称为编辑体的大型超分子复合体中。由于人类没有对线粒体rna进行同样广泛的编辑，因此他们不具备这种编辑复合物，因此，它是理想的药物靶点。我工作的总体目标是开发针对编辑体机制的各个部分的抗锥虫治疗方法。基于物理和化学的计算机辅助药物设计方法可以帮助我们设计出更有效的药物，从而阻止寄生虫的生存。我的主要职业目标是成为R1研究机构的终身教授，并拥有一个充满活力，富有成效和多样化的研究小组。作为一名教师，我的愿景是推动计算机辅助药物设计朝着系统生物学的方向发展，在这种方法中，多种蛋白质和它们结合的rna都是靶标，从而挑战“一种靶标，一种疾病，一种药物”的范式。我设想的新方法将整合多个时间和长度尺度，并明确利用这些算法产生的新结构信息，以创造新的和改进的药物来治疗各种疾病。这些研究将推动我们对生物学理解的重要前沿，最终为更有效的治疗开辟新的途径。在这份申请中，我概述了一个培训、研究和职业发展计划，我相信这将改变计算机辅助药物设计领域，并在我作为一名独立研究者的发展中发挥重要作用。重要的是，K22奖将使我能够在最初的教师生涯中把更多的精力集中在实现这些创新的科学目标上，这反过来将大大提高我获得NIH R01资助并成为终身教授的机会。锥虫是几种毁灭性热带疾病的病原体。每年，数百万人面临这些疾病的风险并遭受这些疾病的折磨，然而，缺乏治疗这些疾病的有效药物。我的工作目标是开发新的和改进的计算机辅助药物设计方法，使发现和开发更好的药物对抗这些疾病。

DESCRIPTION (provided by applicant): The trypanosomes are a group of parasites that cause several devastating tropical diseases, including African sleeping sickness in African and Chagas' disease in Central and South America. Each year, millions of people in the poorest countries are at risk for and suffer from these diseases. Yet, effective drugs to treat these diseases are greatly lacking. The trypanosome parasites possess a unique biological process wherein their mitochondrial RNAs are extensively edited before translation can occur. This process takes places in a large supramolecular complex known as the editosome. As humans do not undergo the same extensive editing of their mitochondrial RNAs, they do not possess this editing complex, thus, it is an ideal drug target. The overall goals of my work are to develop anti-trypanosomal therapeutics that target various parts of the editosome machinery. Physics- and chemistry-based computer-aided drug design methodologies can assist us in our efforts to design more effective drugs that will thwart the parasites' efforts to survive. My main career goals are to become a tenured, endowed professor at a R1 research institution and to have a vibrant, productive, and diverse research group. As a faculty member, my vision is to drive computer-aided drug design towards a systems biology approach, where multiple proteins, and the RNAs they bind, are targeted - thus challenging the "one-target, one-disease, one-drug" paradigm. The new approaches I envision will integrate multiple time and length scales and take explicit advantage of the new structural information these algorithms yield, in order to create new and improved drugs to treat a variety of diseases. These investigations will push important frontiers in our understanding of biology, ultimately opening new pathways to more effective therapeutics. In this application, I outline a training, research, and career development plan that I believe will transform the field of computer-aided drug design and play an essential role in my development as an independent investigator. Importantly, the K22 award will allow me to focus more of my energy on achieving these innovative scientific goals in the initial faculty years, which will in turn greatly improve my chances of securing an NIH R01 grant and becoming a tenured professor. The trypanosomes are the causative agents of several devastating tropical diseases. Each year, millions of people are at risk for and suffer from these diseases, yet, effective drugs to treat these diseases are lacking. The goals of my work are to develop new and improved computer-aided drug design methods, enabling the discovery and development of better drugs against these diseases.