Structure-guided development of potent PfPKG inhibitors for malaria chemoprotection

Malaria is a deadly infectious disease that infects more than 200 million people and kills upwards of 400,000 each year. Child survivors of malaria suffer serious long-term health and cognitive impairment. Thus, the disease imposes a huge burden in terms of both lives lost and socioeconomic development in malaria-endemic countries. The situation is likely to worsen due to the emergence of drug-resistant parasites and insecticide-resistant mosquitoes. Malaria is the top infectious-disease threat facing the U.S. military since it diminishes operational readiness of troops in several overseas areas of operations in Asia, Africa, and the Caribbean. Other Americans traveling to endemic countries for personal, business or government reasons, such as tourists, State Department personnel and Peace Corps volunteers, also need protection from malaria. Eradicating malaria requires new tools for preventing infection. An adult malaria vaccine is still not available (Mosquirix™ is recommended only in children in Africa) and the effectiveness of insecticides is diminished by the emergence of insecticide-resistant mosquitoes. Malaria prevention relies greatly on a few drugs, but these have several drawbacks. Some do not attack the latent forms of the disease or have serious side-effects, e.g., anemia, in large numbers of people. Others are too expensive for widespread use by poor at-risk populations or are challenged by drug resistance in parasites. To make progress against malaria, it is essential that we stay one step ahead of these problems by investing in research into new drugs. Malaria is caused by a parasite, Plasmodium, that is passed to humans by mosquitoes. Within the human host, the parasite begins a multi-stage developmental program in which the liver is first organ to be infected. This stage is the “weakest link” in the parasite’s life cycle because Plasmodium must multiply exponentially within the liver. Success at this stage enables the parasite to increase its numbers and gain a toehold in the body from where it spreads into the bloodstream and causes symptoms. There is belief in the adage “prevention is better than cure.” Previous work identified a parasite protein that is required both for parasite entry and exit from liver cells. Blocking the action of this protein significantly decreases the parasite’s growth in the liver and its ability to enter the bloodstream. Compounds that specifically target this protein will be manufactured and test their ability to block parasitic infection of liver cells will be tested. This work is a collaboration with Department of Defense laboratories at the Walter Reed Army Institute of Research and could lead to the development of new drugs to protect against malaria.

Project Details

Drug-based Strategies
Product Development

Jul 2023 — Jul 2027

$3M

United States