Mechanism for Antimalarial Drug Action Explained

Researchers have found that differences in the way host and parasite replenish an enzyme targeted by antimalarial drugs may explain why the parasite is selectively killed. The enzyme, dihydrofolate reductase-thymidylate synthase (DHFR-TS), has been for many years the target of antifolate therapy against Plasmodium falciparum malaria. A report published in the April 19, 2002, edition of Science describes the molecular basis for the drug action.

The research team, from the University of Washington (Seattle, USA), found that while the drug could inhibit both the mammalian and parasitic enzymes to the same degree, mammalian cells could quickly replenish their supply. On the other hand, tight binding between the enzyme (now inactivated) and messenger RNA in the parasite prevented synthesis of more enzyme. The parasites die from lack of the enzyme while the host cells are able to recover.

This research indicates a shift in how scientists think about treating infectious diseases, improving on many of the increasingly ineffective remedies that are currently used. "We are reinterpreting what has worked well previously, not just through a half-century-old standard for selective drug action but in the context of our most current understanding of how the cell works,” explained Dr. Pradipsinh Rathod. "By combining that reinterpretation with new tools developed in the last few years, we are discovering that there is a lot more to finding drugs that work well.”

Much is being learned from the study of the human genome, and work on the malaria genome is expected to be finished this year, allowing for the first time a direct search for metabolic differences between host and parasite. That in turn will inspire hunts for pharmaceuticals that will selectively kill parasites while doing minimum damage to the host cell.

"Malaria is a big issue because no vaccines have worked,” Dr. Rathod said. "Medications have worked in the past but new ones have to be cheap and they have to be nontoxic. Currently there is not a lot of incentive for drug companies because they think there is no way that they are ever going to recover their investment. We must make the drug-development process more rational and more efficient.”




Related Links:
University of Washington