Recently, major advances have been made in elucidating both the genetics and biochemistry of chloroquine resistance as well as in elucidating the atomic level interactions between chloroquine and its principle target, uncrystallized heme. In the former, groundbreaking advances by the Wellems lab have expanded into a series of detailed studies conducted in our laboratories, as well as by others that have generated enormous data in a short period of time. In the later, major advances have very recently been made by members of this consortium in defining the physical chemistry of quinoline - heme interactions using both new solution NMR methods as well as cutting edge solid state NMR methods. In collectively analyzing these data new (previously unrecognized) concepts that assist the design of quinoline and acridine based antimalarial drugs become evident. Capitalizing on these, while remaining within antimalarial drug cost limitations, also requires significant advances in synthetic chemistry, including developing highly chemo- and regioselective cross-coupling reactions. Over the past 18 months, we have pioneered major advances in the synthesis of heme-targeted antimalarial (HTA) pharmacophores. Our discussions and collaborations in this regard have developed into highly synergistic drug discovery activities between the laboratories of the investigator, Dr. Roepe, and Dr. de Dios. We will combine the unique genetic, biochemical, physical chemical and synthetic chemistry expertise present among our groups to design, synthesize, and solve drug - target structures for new HTA drugs. Using the unique drug screening capabilities present in our consortium, we will analyze large libraries of these for antimalarial activity, both alone and in combinations. Our long term goal is the identification of novel, inexpensive, efficacious therapy for treating drug resistant malaria.
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