Novel approaches to targeted antimalarial development
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Malaria is an ancient disease that has likely plagued mankind for our entire existence. Today, malaria continues to be a leading cause of morbidity and mortality in the developing world, leading to nearly 200 million cases and greater than half a million deaths annually. Although five parasite species are known to infect humans, Plasmodium falciparum is the most pathogenic and is the leading cause of malaria-attributable mortality worldwide. Pathogenesis of P. falciparum is mediated by cytoadherence of infected red blood cells (iRBC) to the endothelium in the host microvasculature or to the fetal-derived syncytiotrophoblast in the placenta. Although parasite binding and sequestration has long been recognized as a key mediator of pathogenesis in severe malaria, limited tools for in vitro analysis of cytoadherent iRBC have considerably hindered our ability to better understand this important parasite mechanism. Current malaria control measures rely heavily on extensive vector control, effective diagnostic testing, and efficacious antimalarial drugs. However, rising parasite resistance to first-line antimalarials places existing control measures in serious jeopardy. All existing antimalarials are small molecule inhibitors and are, therefore, highly vulnerable to the development of drug resistance. Future malaria control efforts will rely on the development of new antimalarials that target essential Plasmodium processes and utilize novel mechanisms of action that are uniquely resilient to parasite mechanisms of drug resistance. In this dissertation, we explore new approaches to targeted antimalarial development that seek to both improve the tools available for in vitro malaria research and provide groundwork for future antimalarial peptide therapeutics. We begin by examining a panel of existing antimalarial and antimicrobial drugs with the overarching goal of identifying a cytostatic agent that will arrest late-stage, adherent iRBC for in vitro adhesion studies. We then proceed into the rapidly growing field of stapled peptide therapeutics as we explore the permeability and activity of these novel targeted antimalarial agents in P. falciparum-iRBC. The results herein provide exciting support for the use of targeted antimalarial therapies both in the control of this widespread global disease and in the understanding of this ancient biological organism.