Towards a Structural Systems Biology Approach for Anti-Trypanosomal Therapeutics

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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.