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.
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 (see the structure) was active in the liver stage of infection. Rresearchers 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.....
