Lead discovery of novel chemotypes effective against relapsing malaria

This proposal addresses the PRMRP Topic Area of Malaria and to two FY21 Areas of Encouragement: (1) identification of novel and/or innovative malaria drug targets for blood and liver stage malaria parasites; and (2) investigation of mechanisms of drug resistance in malaria, to include host, pathogen, and region-specific resistance against drugs used for treatment and prophylaxis. Malaria ranks #4 on the infectious disease threat list created by the Military Infectious Disease Research Program. Every year, malaria infects about 229 million individuals and kills >400,000 worldwide. Plasmodium falciparum (one of the major malaria causing parasites) resistance to the first choice 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. Additionally, there is a significant need for development of safe, potent drugs against Plasmodium liver stage infections, which is the first stage to occur after the mosquito takes a blood meal before transitioning into the disease-causing blood stages. P. vivax parasites can remain dormant as “hypnozoites” in the liver for weeks, months, to years and then reactivate to cause numerous rounds 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, are dependent the host for drug activation and have major safety issues including life-threatening toxicity in certain individuals. This project seeks to identify novel compounds that may act as safe, effective protective drugs to prevent infection and/or disease or safely cure infection, which would enhance Soldier combat effectiveness and aid the global community in malaria eradication. Though collaborations between Walter Reed Army Institute of Research (WRAIR) with the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), and Medicines for Malaria Ventures (MMV), novel chemotypes with protective and curative activity against the dormant liver-stage form have been identified, enabling new approaches and potential targets for development of next-generation anti-relapse drugs. The proposed research project will allow the optimization of these novel validated candidates for selectivity, potency, in vivo efficacy, and drug-like properties to select lead series for preclinical studies. The goal of this collaboration is to leverage the combined biological and chemistry expertise at WRAIR and NCATS (with in-kind support/consultation from MMV) to optimize compounds against the liver-stage forms of malaria.

Project details

Drug-based Strategies
Product Development

Aug 2022 — Jul 2025

United States