New class of compounds would target earliest stages of infection
Researchers have discovered a group of chemical compounds that might one day be developed into drugs that can treat malaria infection in both the liver and the bloodstream. The study, which appears in the Nov. 18 issue of Science, was led by Elizabeth A. Winzeler, Ph.D., of the Scripps Research Institute in La Jolla, Calif., and was partially funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
Caused by four related parasites in the genus Plasmodium, malaria is transmitted to humans via the bite of an infected mosquito. Once the bite occurs, the parasites travel to the liver, where they usually multiply rapidly for about a week without causing symptoms. Symptoms begin when the parasites spread from the liver to the rest of the body through the bloodstream. However, the parasites can lay dormant in the liver for periods ranging from several months to years before an infected person demonstrates symptoms.
Most of the malaria drugs currently in development target the symptomatic, blood stage of infection. To help achieve malaria eradication, however, a drug would ideally treat infection during both the liver and blood stages. Currently, the World Health Organization recommends only one treatment, primaquine, for the initial, liver stage of certain types of malaria infection; however, primaquine and related drugs can cause a dangerous blood disorder among patients with a genetic condition that is common in malaria-endemic regions of the world. Additionally, drug resistance has been reported, which amplifies the need to find new treatment alternatives.
By screening more than 4,000 chemical compounds that had previously shown activity against blood-stage Plasmodium, the investigators searched for a compound that would also inhibit liver-stage parasites and whose protein structure would allow the modification necessary for future drug development. They found that a group of three related compounds, known collectively as the imidazolopiperazine (IP) cluster, fit these criteria. In addition, strains of Plasmodium that had acquired resistance to other malaria drugs were susceptible to the IP cluster.
Using the IP cluster as a foundation, the researchers designed a drug candidate, GNF179, that reduced levels of one Plasmodium species by 99.7 percent and extended survival by an average of 19 days when tested in malaria-infected mice. By examining infected cells, the researchers confirmed that GNF179 was active in the liver stage of infection. The researchers note that while additional studies will be needed to fully understand the drug's mechanism of action and its specific targets within the liver, this study provides a potential starting point for developing new dual-stage antimalarial drugs.
S Meister et al. Exploring Plasmodium hepatic stages to find next-generation antimalarial drugs. Science Express DOI: 10.1126/science.1211936 (2011).
Martin John Rogers, Ph.D., program officer in NIAID's Parasitology and International Programs Branch, is available to discuss this study.
To schedule interviews, please contact Nalini Padmanabhan, (301) 402-1663, [email protected]
NIAID conducts and supports research-at NIH, throughout the United States, and worldwide-to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov/.