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NIH Research Matters

September 13, 2010

Promising Malaria Drug Candidate Emerges

A chemical that rids mice of malaria-causing parasites after a single oral dose may, with further development and testing, lead to a new malaria drug.

Photo of a mosquito.

Health officials have made significant progress in controlling malaria, but the disease still kills nearly 1 million people worldwide every year, mostly infants and young children in Sub-Saharan Africa. The last new class of antimalarials—artemisinins—came into wide use more than a decade ago. Reports of emerging drug-resistant malaria parasites highlight the need for new malaria therapies.

An international research team set out to search for new compounds that are active against Plasmodium falciparum, the most deadly malaria parasite. They were led by Dr. Thierry T. Diagana of the Novartis Institute for Tropical Diseases (NITD) and Dr. Elizabeth A. Winzeler of the Scripps Research Institute and the Genomic Institute of the Novartis Research Foundation. Winzeler’s lab is supported by NIH's National Institute of Allergy and Infectious Diseases (NIAID). The study appeared in the September 3, 2010, issue of Science.

The work began in 2007 in Dr. Winzeler's laboratory. The researchers screened 12,000 chemicals using a customized robotic technique. They identified a chemical with good parasite-killing abilities and the potential to be modified into a drug. It belongs to a new class of chemicals called spiroindolones. Medicinal chemists at NITD synthesized and evaluated about 200 versions of the compound to arrive at one, called NITD609, that could be formulated as a tablet and manufactured in large quantities.

In test-tube experiments, NITD609 killed 2 species of parasites and also proved effective against drug-resistant strains collected from malaria patients. Laboratory tests showed that NITD609 isn’t toxic to a variety of human cells. When given orally to rodents, the compound stayed in circulation long enough to reach levels predicted to be effective against malaria parasites without causing detectable side effects.

The researchers next tested NITD609 in a mouse model of malaria. A single large dose cured all 5 infected mice that received it. Three doses at half that level also cured all the tested mice. None of the comparison malaria drugs were as effective.

To investigate the parasites' ability to become resistant to NITD609, the researchers exposed them to sublethal levels of the compound until drug-resistant strains emerged. They found that resistance results from a single change in a parasite gene that codes for a protein called PfATP4. No other anti-malaria drugs are known to act on the protein.

"From the beginning, NITD609 stood out because it looked different, in terms of its structure and chemistry, from all other currently used antimalarials," Winzeler says. "The ideal new malaria drug would not just be a modification of existing drugs, but would have entirely novel features and mechanism of action. NITD609 does."

It might be possible to develop NITD609 into a drug that could be taken just once. A one-dose regimen would be easier to follow and leave less opportunity for parasites to develop drug resistance than the current standard treatment in much of the world, which involves multiple doses. Winzeler says additional tests in animals are under way and that NITD609 could enter early-stage safety testing in humans later this year.

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Editor: Harrison Wein, Ph.D.
Assistant Editors: Vicki Contie, Carol Torgan, Ph.D.

NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.

This page last reviewed on December 4, 2012

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