Targeting the Plasmodium Proteasome for Prophylaxis and Treatment of Drug-Resistant Malaria in U.S. Military Personnel

This Expansion Award application focuses on malaria, and responds directly to two Areas of Encouragement stated by the Department of Defense (DOD): (1) 'investigation of mechanisms of drug resistance in malaria, to include host, pathogen, and region-specific resistance against drugs used for treatment and prophylaxis'; and (2) 'identification of novel and/or innovative malaria drug targets for blood and liver stage malaria parasites'. This application builds from two prior DOD research awards made to the lead scientist Dr. David Fidock at Columbia University. These projects lead us to propose that the malaria proteasome, essential for protein degradation in parasites, is an ideal and novel drug target that can be used to treat and prevent malaria.

Malaria ranks #4 on the infectious disease threat list created by the Military Infectious Disease Research Program. In responding to this threat, one major unmet need is to develop new drugs to treat Plasmodium falciparum blood stage parasite infections, which kill ~400,000 individuals worldwide. P. falciparum resistance to the first-line drug artemisinin has spread throughout Southeast Asia and emerged in Africa, the Western Pacific, and South America, endangering the lives of U.S. military personnel deployed there. Another critical need is to safely treat P. vivax liver stage infections that develop first before transitioning into the disease-causing blood stages. P. vivax parasites can stall as 'hypnozoites' in the liver for weeks to months and then reactivate to cause multiple bouts of malaria. These relapses are problematic to diagnose and detect in U.S. Service Members and Veterans who were deployed in an endemic area. The current liver stage drugs primaquine and tafenoquine have major safety issues including life-threatening toxicity in 2%-3% of the population born with a condition of 'G6PD deficiency.'

Substantial evidence shows that a parasite protein complex called the proteasome is an outstanding target to design and develop new drugs active against all stages of the parasite life cycle. Our Consortium has three different classes of chemical compounds that selectively bind this target and potently kill blood and liver stage parasites but do not damage human cells. One unique feature is that chemically targeting the parasite proteasome renders it unable to protect artemisinin-resistant or -sensitive parasites from artemisinin action. No other group of antimalarial compounds has this ability to overcome resistance by restoring artemisinin potency. Proteasome inhibitors, unlike primaquine and tafenoquine, do not require G6PD testing. These inhibitors act on both actively growing and hypnozoite liver stage parasites, making them a potentially safe and effective form of prophylaxis that can prevent malaria and eliminate any parasites hiding in the liver.

We now propose a Consortium of academic and DOD researchers that we believe can take the current studies to the next level of delivering compounds that can enter preclinical trials in specialized mouse models of P. falciparum infection, and onto clinical trials of P. falciparum and P. vivax malaria. Our Consortium combines the three leading chemistry groups who have developed three distinct sets of Plasmodium-specific proteasome inhibitors. These teams are led by Drs. Matt Bogyo (Stanford University), Bill Gerwick (University of California San Diego [UCSD]) and Gang Lin (Weill Cornell Medical College). These chemists are joined by Drs. David Fidock (Columbia University), Anthony O'Donoghue (UCSD) and Laura Kirkman (Weill Cornell), who provide expertise in antimalarial drug discovery, parasite biology, genetics, and biochemistry. Our Consortium also includes Dr. Alison Roth from the Experimental Therapeutics Branch at the Walter Reed Army Institute of Research (WRAIR), who brings outstanding expertise in testing compounds for activity against blood and liver stage parasites, including hypnozoites in the P. vivax-like parasite P. cynomolgi.

Our project begins with medicinal chemistry-based efforts to improve on the existing chemical structures by identifying areas of potential improvement, such as increasing their potency, optimizing their binding specifically to the parasite proteasome and not its human counterparts, reducing any host toxicity, increasing drug uptake, improving solubility, and extending how long the drugs remain in a patient's circulation. Refining these compounds will be guided by biochemical assays that examine binding to purified parasite proteasomes and measurements of inhibitor activity against Plasmodium blood and liver stage parasites. These results will help guide further rounds of chemistry. Promising compounds then advance into rodent malaria models. By the end of this 2-year project, our goal is to have compounds that are ready to move into advanced preclinical and clinical testing. We are enthusiastic about the prospects of delivering candidate medicines that can effectively and safely treat and prevent malaria in U.S. military personnel deployed to malaria-endemic regions.