Dr. Riscoe’s Experimental Chemotherapy laboratory focuses on the discovery, optimization and translational development of antiparasitic drugs, especially drugs for treatment and prevention of malaria, a severe and potentially fatal tropical disease. Using modern methods of drug design and chemical synthesis his laboratory has successfully created 5 novel antimalarial “chemotypes” with exemplary molecules in each category that are orally bioavailable and curative in mouse models of infection. The Portland VA and neighboring OHSU have filed for patent protection on all 5 chemotypes which include: 1) Dual functional acridones with blood stage activity that interact synergistically with many standard antimalarial agents, 2) 4-Aminoquinoline derivatives (including “Pharmachins”, “Amodiachins” and bis-Quinolines referred to as “APQs”), designed to replace chloroquine, that are rapidly active against multidrug resistant strains of Plasmodium falciparum parasites, 3) Quinolones (i.e., ELQ-300) that block parasite mitochondrial respiration and act vs. the blood, liver, gametocyte, and vector stages of parasite development, 4) Prodrug ELQ-331 (MMV-167) for once-weekly dosing and for injectable sustained- release seasonal protection against malaria, and 5) Next generation 3-biaryl-ELQs such as ELQ-596 and prodrug ELQ-598 with enhanced potency, efficacy and pharmacokinetics for once-monthly dosing and protection from malaria. There is a new effort in Dr. Riscoe’s lab to design new 3-biaryl-ELQs that target not only the replicative life cycle stages of malaria but also the recalcitrant hypnozoite stage of vivax and ovale malaria. Prototype 3-Biaryl-ELQs are presented in this RCS renewal application in which the prodrug releases the active ELQ molecule upon activation by the liver’s P450 system but also a chemical inducer that “springs” from the promoiety. Such dual warhead ELQ prodrugs are being studied as part of the PI’s VA funded research laboratory. It is noteworthy that ELQs (e.g., ELQ-316) are also potent against other parasites including Toxoplasma gondii and Babesia microti with proven activity demonstrated in vitro as well as in vivo. T. gondii is a eukaryotic intracellular parasite estimated to have infected billions of people worldwide, placing them at risk for toxoplasmosis. Fetuses and immune-compromised persons (e.g., HIV patients, transplant patients, and individuals undergoing cancer chemotherapy) are susceptible to severe toxoplasmosis, which can be fatal or lead to permanent ocular or neurologic disability. Even healthy people without immunodeficiency are susceptible to ocular disease which may cause vision loss. B. microti causes babesiosis which is transmitted by ticks. It is endemic in the New England region of the United States where it is called, “Nantucket Fever”. Like malaria and toxoplasmosis, babesiosis is a potentially fatal infection and new and effective drugs are urgently needed. It is noteworthy that B. microti is a common co-infection associated with Lyme disease and is regarded as the foremost infectious risk to the U.S. blood supply. Dr. Riscoe’s VA Lab also investigates drug mechanism of action by use of methods that are traditional to the fields of biochemistry, chemical biology and molecular parasitology. Dr. Riscoe’s laboratory receives research funding from the Department of Veterans Affairs, the US National Institutes of Health, and the Medicines for Malaria Venture (Geneva) and he maintains an active collaboration with members of the Division of Experimental Therapeutics at the Walter Reed Army Institute for Research. He continues to serve as an invited reviewer for the US DOD’s Peer Reviewed Medical Research Program (PRMRP) and the NIH. The long-term objective of Dr. Riscoe’s malaria research program is to develop drugs that are inexpensive, safe and effective in prevention and treatment of the most vulnerable populations, young children and pregnant women, and ultimately to develop a cocktail of drugs that may be used to eradicate the disease. Effective chemo-preventative countermeasures to malaria will help to avoid unnecessary toxic exposures (i.e., febrile conditions compounding the stress of warfare and combat readiness) that may otherwise have enduring long-term health consequences for US veterans.

U.S. servicemen and women encountered malaria during the Revolutionary War and every US war since that time. Malaria and antimalarials are two of the most common biological and chemical exposures of US combat veterans. Multidrug resistant parasites have spread to virtually all malarious regions of the world. New drug strategies for prevention and treatment of malaria are urgently needed. My lab is committed to the development of safe and effective drugs that can be used in all individuals, regardless of their station: children, adults, men, women, pregnant, unborn, or genetically deficient in the enzyme glucose 6-phosphate dehydrogenase (G6PD). Some existing antimalarial drugs have psychiatric side effects or are toxic in individuals with G6PD deficiency. The drugs that we design are engineered to be safe for both treatment and prevention of malaria. The resultant advantages of avoiding drug toxicity, febrile illness, and complex medical management during deployment are self-evident, as are the benefits to both short and long-term health of the warfighter and future veteran.