ODU Researchers Take Aim at Malaria in Two New Studies
Roland Cooper, an Old Dominion University assistant professor of biological sciences and a prominent malaria researcher, is a member of two research teams that have reported advances against the mosquito-borne disease in recent weeks.
A paper published in early April in the prestigious international journal Nature reports the design of a "double-whammy" drug that is a potent new agent against the human malaria parasite Plasmodium falciparum. Cooper and his former master's student at ODU, Kristin Lane, were co-authors of the paper. Jane Kelly, a researcher at Portland State University in Oregon, led the research team.
Cooper and a Ph.D. student that he advises, Carmony Hartwig, led a collaboration with Johns Hopkins University's Gary Posner on another study published in February in the journal Biochemical Pharmacology. This article focuses on the long-used, but little understood malaria drug artemisinin, which is derived from the Sweet Wormwood plant.
Last year, Cooper and two collaborators from Notre Dame University and Georgetown University received a $1.25 million grant from the National Institutes of Health for a five-year study of the drug resistance of the lethal malaria parasite. "We are studying how 60 years of intense drug pressure has reshaped the genome of P. falciparum, which kills about 1 million people each year, mainly children in sub-Saharan Africa," Cooper said.
The malaria parasite infects the red blood cells of its host and is transmitted from person to person by mosquitoes. No vaccine for malaria exists, and the lack of affordable, effective drugs for people in developing countries is the main reason for the large numbers of annual deaths.
"Compounds such as quinine and artemisinin have been used for centuries to cure malaria, but we still do not have a good understanding of how these drugs kill the parasite," Cooper said. "There are only a few isolated reports of resistance to artemisinin in southeast Asia. However, since this drug will be the mainstay of chemotherapy for the next decade, resistance is expected to spread. Already, the parasite's resistance to quinine and other drugs is the single greatest obstacle towards malaria control in the endemic regions of the world."
The study reported in Nature describes a drug that not only can kill the malaria parasite, but also seems to keep it from developing resistance to quinine. The new drug, an innovative acridone design called T3.5, "merges intrinsic potency and resistance-counteracting functions in one molecule, and represents a new strategy to expand, enhance and sustain effective antimalarial drug combinations," the paper states.
An article about the breakthrough was prepared for Reuters and distributed internationally under the headline: "New malaria drug fights resistance, helps others."
T3.5 is relatively inexpensive to make, has a good safety profile and appears to be highly potent against drug-resistant and non-drug-resistant versions of the malaria parasite in laboratory culture studies and in rodent malaria models, Cooper explained.
The new drug targets the iron-containing pigment heme, which develops when the parasite digests the hemoglobin in blood. The iron content would be lethal, but the parasite can convert it to a nontoxic form. Compounds such as quinine can stop this conversion, but the parasite has come up with a way to eject malaria drugs. T3.5 both keeps the heme toxic to the parasite and stops it from pumping drugs out.
Cooper and Hartwig's work that is reported in Biochemical Pharmacology explores how artemisinin works against P. falciparum. Knowing why the drug is effective would be of critical importance if the parasite does develop resistance to the drug.
Using a series of novel fluorescent artemisinin derivatives synthesized by the Posner group at Johns Hopkins, Hartwig conducted the first extensive study of the intracellular localization of artemisinin in living, human malaria parasites. The research found that the drug acts as a strong oxidant, damaging cell membranes.
"The drug takes advantage of the parasite's need to feed on the hemoglobin," Cooper said. "Digestion of hemoglobin releases large amounts of iron-containing heme, which interacts with the endoperoxide group of the artemisinin to form free radicals," which can attack the parasite.