Malaria is a devastating disease that affects over one billion people and causes approximately 1 million deaths annually. Although there are a number of drugs used to treat the disease, resistance to these drugs is becoming more widespread. Superior long-term solutions for combatting resistant parasites require identification of novel antimalarial drug targets and compound classes that kill the parasite with unique mechanisms of action. Plasmodium falciparum, the most deadly species to humans, as well as other malaria- causing species of Plasmodium, have multiple aspartic proteases that are essential to the parasite's survival. We propose to (1) optimize the antimalarial activity of two classes of asparti protease inhibitors and (2) determine their unique mechanism of action as antimalarial agents. Through our preliminary collaborative efforts, we have already identified drug-like aspartic protease inhibitors with inherent antimalarial activity and oral efficacy for suitable optimizationas drugs. In order to efficiently address the critical need for novel antimalarials, the Center for World Health &Medicine (CWHM) at Saint Louis University has established a research collaboration with the Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences. CWHM is a non-profit institute comprised of highly skilled and successful former Pfizer drug discovery scientists with expertise in the translation of basic science into the discovery and development of novel drugs for challenging targets. GIBH is a leading Chinese center of expertise in malaria biology, drug discovery and medicinal chemistry. This unique collaboration encompasses the expertise and resources necessary to successfully demonstrate the viability of novel aspartic protease inhibitors as antimalarial agents and to determine of thei mechanism(s) of action for target-based drug discovery.

Public Health Relevance

Superior long-term solutions for combatting the drug-resistant parasites that causes malaria, which kills a million people each year, require identification of new antimalarial drugs that kill the parasite in new ways. With the drug discovery expertise of scientists at the Center for World Health &Medicine at Saint Louis University and the malaria expertise of scientists at the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, this project collaboration will investigate the potential of novel classes of antimalarial drugs to treat drug-resistant parasites and identify the mechanisms by which these drugs kill the parasites.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1)
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Mcgugan, Glen C
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Saint Louis University
Schools of Medicine
Saint Louis
United States
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Meyers, Marvin J; Anderson, Elizabeth J; McNitt, Sarah A et al. (2015) Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents. Bioorg Med Chem 23:5144-50
Meyers, Marvin J; Tortorella, Micky D; Xu, Jing et al. (2014) Evaluation of aminohydantoins as a novel class of antimalarial agents. ACS Med Chem Lett 5:89-93