Current estimates from the World Health Organization suggest that global cases of infectious disease are rising. Malaria remains a devastating disease in poor and undeveloped countries in Africa, South America and Asia, where nearly one million deaths were reported in 2009. In these areas, parasites can rapidly develop drug resistance, which erodes the efficacy of antimalarials. Thus new drugs and the identification of novel targets are desperately needed to treat malaria. My graduate studies with Prof. Michael Marletta (UC Berkeley) involved detailed mechanistic studies on enzymes that are important to human health. To learn more about infectious disease and chemical biology I joined Prof. Jon Clardy's lab at Harvard Medical School (HMS). At HMS I received training to work with both the blood and liver stages of the malaria parasite. This training allowed me to develop a high-throughout screen to identify inhibitors of liver stage malaria. In the next two years I plan to screen several small molecule libraries for potential therapeutics to treat malaria (Specific Aim 1). During my time at HMS I will also train with several experts to learn how to generate genetic knockouts in malaria, raise drug resistant parasite strains, and maintain transgenic mosquito lines. I can then use this training to evaluate the biological processes of the parasite that my identified liver stage malaria inhibitors target (Specific Aim 2) and to biochemically characterize the protein targets (Specific Aim 3). The training needed to address Specific Aims 2 and 3 will be completed at HMS during the K99 phase of the award, but most of the experiments will be completed during the independent phase of the award. I plan to apply for a tenure-track academic position with the goal of leading a research group focused on characterizing essential processes and proteins of the malaria parasite that facilitate the disease process. HMS is ideally suited for the proposed K99 training period as it has a state-of-the-art high- throughput screening facility and is a leader in infectious disease research with programs like the Harvard Malaria Initiative. I believe the courses and training I receive in the next two years will broaden my understanding of parasite biology and nicely complement my previous skills in enzymology to make me uniquely suited to work on global infectious disease as an independent researcher.
Malaria is a life-threatening disease that is caused by infection from a protozoan parasite. I plan to advance antiparasitic drug discovery and the current understanding of Plasmodium biology by using small molecules to probe for essential parasite processes.
|Posfai, Dora; Eubanks, Amber L; Keim, Allison I et al. (2018) Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity. Antimicrob Agents Chemother 62:|
|Totzke, Juliane; Gurbani, Deepak; Raphemot, Rene et al. (2017) Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-? Inhibition for Cancer and Autoimmune Disease. Cell Chem Biol 24:1029-1039.e7|
|Raphemot, Rene; Posfai, Dora; Derbyshire, Emily R (2016) Current therapies and future possibilities for drug development against liver-stage malaria. J Clin Invest 126:2013-20|
|Herman, Jonathan D; Pepper, Lauren R; Cortese, Joseph F et al. (2015) The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Sci Transl Med 7:288ra77|
|Raphemot, Rene; Lafuente-Monasterio, Maria J; Gamo-Benito, Francisco Javier et al. (2015) Discovery of Dual-Stage Malaria Inhibitors with New Targets. Antimicrob Agents Chemother 60:1430-7|
|Derbyshire, Emily R; Min, Jaeki; Guiguemde, W Armand et al. (2014) Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites. Antimicrob Agents Chemother 58:1516-22|