May 19, 2010 | 4
Malaria kills hundreds of thousands of people every year, and the malaria parasite Plasmodium falciparum is behind a majority of those deaths. Although newer drug combinations (of artemisinins) proved effective after resistance to widely used treatments appeared, hints of resistance to this newer therapy are also beginning to emerge, creating a darkening cloud over a field already beset with challenges.
Two new papers, published online May 19 in Nature, present thousands of new possible compounds to fight the persistent parasite (Scientific American is part of Nature Publishing Group).
David Fidock, of the Department of Microbiology and Immunology and the Department of Medicine at Columbia University Medical Center, wrote in an accompanying essay in the same journal that the results "merit celebration." The candidate compounds likely have "the potential to be developed into tomorrow’s antimalarial drugs," he continued.
Both new studies screened hundreds of thousands of chemical compounds to see if they would stop or slow the parasite’s asexual blood-based growth phase. One of the benefits of mass screening is that it allows researchers to test a vast number of compounds without exhaustive knowledge—or even many assumptions—about the biology of the target. So if a compound works against the parasite and is safe for the host, a new treatment could go to market even before the mechanisms behind its success are fully understood.
One team of researchers, led by W. Armand Guiguemde of the Department of Chemical Biology and Therapeutics at St. Jude Children’s Research Hospital in Memphis, Tenn. found 172 promising candidates among 309,474 unique compounds that were screened. The researchers also discovered that several of these candidates were effective against strains that had developed resistance to other drugs, such as chloroquine and atovaquone, suggesting that "these compounds do not share mechanisms of resistance." The group tested one compound in a mouse model and found it inhibited 90 percent of the parasite after three days of treatment. (Fidock pointed out, however, that the amount of this new compound needed in the mouse was "25-fold higher than the effective dose of chloroquine in the same animal model.")
The other group, led by Francisco-Javier Gamo of GlaxoSmithKline’s Tres Cantos Medicines Development Campus in Spain, screened 1,986,056 compounds from the company’s library. The team found more than 13,000 that halted growth of the parasite by 80 percent—with more than 8,000 of these working on a strain that was resistant to other drugs. Gamo’s group proposed that some of the chemicals might be working on the kinase enzymes of the parasite, which play a big role in determining cellular structure and signaling. Research is underway on kinase-targeted medications for other diseases, from arthritis to cancer, which means this line of antimalarial investigation might intersect with ongoing work in other fields, Fidock noted.
Although Gamo et al. did not describe any tests in vivo, the company is making available more than 11,000 of the new compounds (which had been proprietary chemicals of GlaxoSmithKline) to researchers via a searchable European Bioinformatics Institute database. "It is momentous that a large pharmaceutical company has made its antimalarial drug discovery data, including chemical structures, freely available," Fidock wrote.
Nevertheless, "malaria control," Fidock wrote, "is at a pivotal stage," with resistance a constant threat and hundreds of millions of new malaria cases each year. He added that these two new papers will help replenish the antimalarial drug development pipeline, which had been "woefully thin." To be sure, however, the pipeline remains long, and moving early compounds to distributable drugs will require considerable time and trials—but hopefully few tribulations.
Image courtesy of iStockphoto/b79