Identifying New Chemical Entities that Treat and Prevent Relapsing vivax and Drug-Resistant falciparum Malaria in U.S. Military Personnel

Malaria is one of the highest infectious disease priorities for the US Military and the Military Infectious Disease Research Program (MIDRP). Infection by the malaria pathogens Plasmodium falciparum and P. vivax begins with the bite of an infected mosquito. Injected parasites migrate to the liver where they develop inside hepatocytes. Subsequently, liver stage parasites emerge into the blood stream and infect red blood cells, causing disease symptoms that can be lethal in non-immune individuals who are not treated with effective drugs. P. vivax liver stage parasites can also form dormant 'hypnozoites' that can reactivate weeks or months later to reinitiate development and cause malaria relapses, even long after US Military troops have left an endemic area.

Choices of prophylactic drugs licensed by the Food and Drug Administration for the prevention of falciparum and vivax malaria are few, and these drugs are under constant threat of parasite resistance, along with other problems associated with drug tolerability, compliance, and side effects. Licensed malaria treatment drugs are also few in number, and are similarly compromised by resistance. Most antimalarial drugs do not have activity against liver stage parasites and thus are not suitable for prophylactic prevention of disease in malaria-exposed US Army personnel. None of the currently licensed prophylactic drugs that are permitted for use in US troops can be dosed weekly, which raises major compliance issues. Treatment for relapsing P. vivax malaria is complicated for some patients as only one class of drugs, the 8-aminoquinolines, is effective against hypnozoites. This drug class, however, can cause severe side effects of hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency (prevalent in 10% of the African American population or 2%-3% of the US Military). Primaquine has been recently shown to be ineffective against vivax malaria without activation by a liver enzyme, CYP 2D6, which is deficient in 10% of the US population (potentially affecting 10% of the military force). Past problems with drug compliance as a consequence of drug side effects have led to malaria infections in deployed Soldiers that have rendered entire units combat-ineffective (e.g., Liberia 2003) or led to deaths of US Soldiers (e.g., Liberia 2009).

Once again, US forces are deployed to Western Africa to assist with the Ebola epidemic, and in addition to the Ebola threat, they will face endemic malaria as a well-known consequence of deployment to this country. Given the lack of an effective vaccine for any species of malaria parasite, continual investment in development of novel chemical scaffolds for malaria prophylaxis and treatment is necessary. Finding chemical scaffolds with activity against both liver and blood stage malaria will provide a starting place for the next generation of antimalarial drugs suitable for prophylaxis and treatment of both falciparum and vivax malaria.

We propose a closely coordinated, collaborative project to discover new chemical agents that can be developed into future medicines to prophylactically prevent or cure malaria. Our consortium includes a highly qualified, enthusiastic, and complementary team of biologists and chemists from the Columbia University Medical Center (CUMC), the Walter Reed Army Institute of Research (WRAIR), and the National Center for Advancing Translational Sciences (NCATS). Dr. David Fidock, a Professor of Microbiology and Immunology and of Medical Sciences at CUMC, and LTC Norman Waters, a Director in the Military Malaria Research Program at WRAIR, serve as Initiating and Partnering Principal Investigators, respectively. The starting point for our project is the identification of over 2,000 compounds that potently inhibit the growth of laboratory-cultured drug-resistant P. falciparum blood stage parasites. Through additional assays, we aim to identify another 1,000 active compounds. These sets of compounds will be tested against liver stage parasites, using a rodent malaria model species. Compounds will also be assayed for evidence of toxicity and also for their suitability as candidate pharmaceuticals. Favorable compounds that emerge from these assays will be tested for their ability to eliminate the hypnozoite forms that are characteristic of P. vivax, using the closely related species P. cynomologi. Compounds that successfully pass through our screening funnel will then be optimized through additional chemical refinement and assays that measure changes in potency and chemical properties. At the conclusion of our project, we aim to have 1-3 chemical series that are effective at preventing and curing malaria. Successful outcomes will lead to further work that prepares the most advanced compounds for efficacy studies in human volunteers, with the ultimate objective of developing prophylactic and curative medicines to protect US Military personnel exposed to malaria.