News Release

Protein research illustrates how drugs fight malaria, other diseases

Peer-Reviewed Publication

University of Washington

Parasite-caused diseases such as malaria kill millions of people each year, and eradication efforts have been largely futile.

But developing a clear understanding of how to exploit emerging information from genome research is the first step in developing effective, safe and affordable drugs that can combat many such diseases, said Pradipsinh Rathod, a University of Washington chemistry professor.

For instance, understanding how a single protein called DHFR is regulated in mammals and how it functions differently in the malaria-causing parasite Plasmodium eventually could mean a breakthrough in identifying other good targets for attacking Plasmodium and ultimately killing the deadly pathogen, Rathod said.

Rathod and former graduate student Kai Zhang, now a post-doctoral researcher at the Washington University School of Medicine in St. Louis, are co-authors of a paper detailing the work in the April 19 edition of the journal Science.

The work supports a shift in how scientists think about treating infectious diseases, improving on many of the increasingly ineffective remedies that are currently used, Rathod said.

"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," he said. "By combining that reinterpretation with new tools developed in the last few years, we're discovering that there's 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 on an unprecedented scale, Rathod said. That in turn will inspire hunts for pharmaceuticals that will selectively kill parasites while doing minimum damage to the host cell.

"But such efforts will be futile if our models for selective drug action are incomplete," he said.

In the current research, Zhang and Rathod found that parasites are sensitive to drugs that target their DHFR in part because of their inability to rapidly replenish the dead enzyme. Host cells, on the other hand, can rapidly generate excess amounts of the DHFR protein if the drug accidentally enters the host cell. Previously, it was believed the different effects between parasite and host were entirely related to how tightly the drug used against the parasite was bound to the DHFR protein in the parasite.

The latest research offers a new standard for selective targeting, Rathod said. He likens it to the military establishing a battle plan based on good intelligence.

"You can have all the maps, you can have all the guns, you can have all the firepower, but if you don't know where the important targets are, it's a waste. You can do as much harm as good," he said.

The Science paper focuses on malaria, a disease that each year strikes one-seventh of the world's population – 900 million people, mostly in southern Asia, sub-Saharan Africa and central and South America – and kills 2.7 million people.

However, the same concepts could apply to research into, for example, HIV, cancer, heart disease or Alzheimer's disease, Rathod said. The goal is finding the means to attack certain kinds of cells in ways that aren't toxic to other cells, even cells similar to the ones being attacked.

Malaria is the focus of research in Rathod's lab because it is so widespread and often affects some of the world's poorest populations. In some parts of Africa, for example, many people infected with malaria would be hard pressed to pay even $10 a year for medication, Rathod said. Solving a problem of that magnitude will require scientists, drug manufacturers and social agencies to work together, he said.

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

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For more information, contact Rathod at (206) 543-1653, by cellular phone at (240) 472-0881 or at rathod@chem.washington.edu.

NOTE: Rathod is traveling until Thursday but will check e-mail periodically and can be reached by cell phone.


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