A modest laboratory on the third floor of Portland State University’s Science Building 1 has developed a molecule that could save millions of human lives.
Chemistry professor David Peyton’s research team has modified chloroquine, a drug that was once the world’s most successful malaria treatment. Chloroquine needs modification because the lethal malarial strain, Plasmodium falciparum, has mutated and become resistant to the drug.
"The [malaria] parasite came up with a mechanism essentially to pump chloroquine out [of the blood cell] ?” it pumped it out like a sump pump," said Peyton.
Malaria deaths have skyrocketed as a result. In some regions of Africa, malaria mortality has sextupled. The disease currently claims more than a million lives a year.
"The increasing prevalence of chloroquine resistance is the single most important reason that malaria is a re-emerging disease across the globe," said Dr. Donald Krogstad, chair of tropical medicine at Tulane University and Director of the Center for Infectious Diseases at Tulane University.
Other antimalarial drugs exist, but none as cheap and safe as chloroquine. The drug costs approximately twenty cents for a three-day regimen and is gentle enough to give to small children.
"Chloroquine was the most useful drug against malaria and in some ways the most useful drug in the world," said Peyton. "It was the gold standard of what a drug ought to be."
Dr. Catherine Gurski, a local naturopathic physician who used to live in Africa, said that many other malaria drugs are harsh and toxic to the liver ?” not something doctors like to prescribe to small children or pregnant women. Still, small children need antimalarial medicine more than most. Seventy percent of malaria fatalities are children under age five.
Other malaria medicines cost more than chloroquine. One of the most popular contemporary treatments, a derivative of sweet wormwood, costs $2.40 per treatment ?”twelve times the cost of chloroquine. The cost places it out of reach of many of the world’s poor.
To make malaria treatments more affordable again, Peyton decided to try and rehabilitate chloroquine a year and a half ago.
An antidepressant drug named imipramine is known to reverse the resistance to chloroquine. The two drugs taken together comprise a safe and effective treatment, but are too expensive for many malaria sufferers worldwide. Peyton said he wondered if chloroquine and imipramine could be soldered into a single molecule.
Together with a team of graduate and undergraduate students, Peyton began tinkering with the molecules. By late summer 2005, a chloroquine-imipramine hybrid was born. The new compound, featuring the two original substances linked by a nitrogen atom, was named PL01 (Peyton Lab #1).
PL01 succeeded in killing drug-resistant P. falciparum in cell cultures. It has also cured malaria in limited mouse trials at Portland’s Veterans’ Hospital.
"When we administered the original molecule to mice, we gave them quite a lot of it, and there were no side effects whatsoever. That was pretty exciting," Peyton said. "There was no quivering, there was no antisocial behavior, they stayed well-groomed. They were happy mice."
The team wrote up their research and presented it at a Washington, D.C. meeting of the American Society for Tropical Medicine and Hygiene last December.
Since then, the team has cooked up dozens of new chloroquine-imipramine hybrids. PL01 was a "proof of concept," but it was not water-soluble and thus not a viable malaria drug. The 58th hybrid molecule, however, is both water-soluble and potent. It is eight times as strong as chloroquine alone.
Peyton hopes that PL58’s potency could make it a cheap therapy.
"If we can get the dose down to one-tenth of chloroquine’s," he said, "perhaps if the drug costs ten times as much to make, it can still cost 20 cents for a curative dose. That’s my dream."
"[Peyton’s research] looks encouraging," said Dr. Geoff Butcher, a parasitologist from the Imperial College of London, adding that it was too early to draw conclusions. "Lots of compounds work in vitro but are hopeless in vivo, and trials in mice are only the beginning."
Peyton said that PL58’s development is in its infancy. "Drug development often takes as long as a decade," he wrote in an email. "It all seems to be a huge undertaking, but there are recent examples of academic labs doing this sort of thing successfully."
Modified chloroquine may not be the disease’s definitive cure.
"I think in the long term a vaccine is what is required," said Dr. Butcher.
Even so, there is hope that this new treatment could be a powerful tool in the struggle against malaria.
"I feel optimistic about any new approach that offers a distinct strategy from the current prevailing one. The way to beat malaria is to integrate a variety of approaches ?” drugs, anti-mosquito interventions and vaccines ?” with multiple strategies for each," said Dr. Colin Sutherland, Senior Lecturer at the London School of Hygiene and Tropical Medicine’s Malaria Reference Laboratory.
PL01 was the subject of an article in this August’s online Journal of Medicinal Chemistry.