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Therapeutics for Rare and Neglected Diseases

Development of Malaria Transmission-Blocking Drugs

Mosquito

Malaria is a parasitic disease that spreads through the bite of an infected mosquito. Malaria affects an estimated 250 million people worldwide, particularly in the tropical regions of Sub-Saharan Africa. The disease affects multiple organs in the body, and symptoms include cycles of chills, fever and sweating along with headaches, tiredness, muscle pain, vomiting and diarrhea. Current therapies generally lead to complete recovery, but approximately 650,000 patients die each year. Even while on current therapies, patients remain infectious for a period of time, allowing further mosquito-borne transmission to others. The purpose of this project is to develop a novel class of drugs that will not only prevent infection and relieve symptoms but also block mosquito-borne transmission from person to person.

Scientific Synopsis

Control of parasite transmission is critical for elimination and eradication of malaria. However, most antimalarial drugs are not active against sexual stage P. falciparum parasites — called gametocytes — which are responsible for the spread of malaria from person to person via mosquitoes. To begin to fill this void, investigators screened 5,215 known bioactive compounds and approved drugs for gametocytocidal activity. One compound with favorable pharmacokinetics, Torin2, was selected as the first candidate for further evaluation, including testing in an in vivo rodent malaria transmission model. Two 4 mg/kg doses completely blocked parasites’ ability to infect mosquitoes, and a 2 mg/kg dose gave a partial blockade, confirming the transmission-blocking activity of Torin2.

Preliminary data indicate that the Torin2 target in P. falciparum is distinct from the mammalian target, which means researchers can design malaria-specific derivatives. Investigators used a gametocyte viability assay, a cellular mTOR assay and an in vivo rodent malaria transmission model to identify new malaria-specific Torin2 analogues. The goal of this project is to further optimize the Torin2 series and advance a drug candidate through pre-clinical development and early clinical development.

Lead Collaborator

Uniformed Services University of the Health Sciences, Bethesda, Maryland
Kim Williamson, Ph.D.

Public Health Impact

Although current antimalarial treatments are effective, malaria still causes considerable numbers of deaths each year. Moreover, resistance to current therapies is a growing concern. Global health authorities have placed a high priority on developing new strategies for the control and elimination of malaria parasites. Developing a new class of drugs that not only treat the disease but also prevent its patient-to-patient spread would be an important step toward the goal of eradication.

Outcomes

Pilot studies between the lead collaborator and NCATS scientists resulted in identification of a series of compounds suitable for lead optimization. The TRND team initiated a comprehensive pre-clinical project plan, performing medicinal chemistry optimization to identify a lead candidate for further development. Initial pharmacology and absorption, distribution, metabolism and excretion (ADME) studies are being performed, with further studies planned to support filing an Investigational New Drug application with the Food and Drug Administration.

Publications

In vitro evaluation of imidazo[4,5-c]quinolin-2-ones as gametocytocidal antimalarial agents, Bioorg Med Chem Lett., 2016 Jun 15, 26(12):2907-11

Last updated: 09-06-2017
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