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A Double Dose of Hope

Michael Glenwood

A Double Dose of Hope (continued)

"Old" Drugs, New Tricks

Three flights down from Bosch's lab, David Sullivan takes a very different tack. Rather than design a malaria drug from scratch, like Bosch, he is looking for one that already exists but has been used for a different purpose.

The current total pharmacopoeia of approved or experimental drugs contains about 10,000 items, says Sullivan. And within that enormous trove, he believes, there surely reside drugs that have as yet unrecognized powers to kill Plasmodium. To identify such hidden pearls, he advocates screening massive collections of drugs. Since the compounds in such drug libraries have already ascended the arduous FDA approval process or been approved for clinical trials, the approach can save enormous amounts of time and money. (Scientists will not waste time on a drug that is toxic or has serious adverse effects.)

"If you want to develop a new drug, you're going to fail more than 90 percent of the time," says Sullivan. "That's the reality of the process."

It can take 10 to 15 years and cost hundreds of millions of dollars to move a drug from bench to bedside, he explains. Most of the candidate malaria drugs do not make it that far.

"Look at the odds," he says. A scientist might mix a certain drug with an enzyme used by Plasmodium and show that the drug inhibits the enzyme. However, the drug might not be able to penetrate the parasite. Or, if it can get into the parasite, it may not work in an animal model. Then, he says, "the biggest hurdle is taking [drugs] that work in mice and pushing those forward to be drugs that work in humans. We have many agents that work beautifully in mice," he notes, that don't cure malaria in people.

So he'd rather seek from among those drugs that are already approved for human use. Recently, for example, he has been conducting studies on FBS0701. The drug is an iron chelator; it binds and removes excess iron from the body, and it is currently in clinical trials as a possible treatment for iron overload (a condition that can occur in certain diseases that require repeated blood transfusions). But Sullivan believes it also has potential as an antimalarial. Plasmodium requires iron to reproduce. So by binding up free iron, FBS0701 would cut off the supply of an element essential to the parasite's survival.

While there are other iron chelators already in clinical use, they must be given intravenously. FBS0701 can be taken by mouth. Moreover, Sullivan hopes, the drug would target the earliest stage of Plasmodium infection, when the parasites are invading the liver. At this stage, fewer parasites are present and a lower dose would be required.

Sullivan has tested the drug in Plasmodium-infected mice and shown that a single dose cures lethal infections. "We can even give the drug a couple of days before we infect the mice, and it works," he says.

Those results are promising, says Sullivan, and he is currently drafting a paper about these findings. Since FBS0701 is already in Phase 2 clinical trials as a treatment for iron overload, Sullivan has a head start on his antimalarial studies.

Despite the apparent promise of FBS0701, Sullivan emphasizes that the drug is still a long way from being ready for human use. "I temper my excitement every day," he says. "We like to say 'cautious optimism.' I've seen a lot of promising drugs die on the vine."

About five years ago, with resistance to chloroquine rising, he and a Hopkins MD/PhD student named Curtis Chong decided to search for alternatives to that antimalarial. Their strategy was to do a systematic search—take a whole bunch of already approved drugs and see if any would rid infected cells of Plasmodium. Over two years, the scientists procured 2,687 different drugs (a collection that eventually became the Johns Hopkins Clinical Compound Library) and tested the ability of each to inhibit the parasite.

Sullivan and Chong had some promising leads, in particular an antihistamine called astemizole. In test tube studies it inhibited the growth of chloroquine-resistant Plasmodium and, in infected mice, it significantly reduced the level of infection. However, there were problems. A dose of astemizole killed only about 100 malaria parasites in a 48-hour period, whereas an equivalent dose of artemisinin could kill 10,000. That's important, says Sullivan, considering that a malaria patient showing symptoms can harbor about a trillion parasites. So in the end, says Sullivan, "we did not find the pearl."

Still, Sullivan continues to have faith that "repurposing" old drugs can yield new cures for a raft of diseases, not just malaria. A good portion of the Johns Hopkins Clinical Compound Library, he notes, is available to any scientist who wants to screen it in search of a drug for a particular disease of interest. A sample of each of the available 1,500 drugs can be dispensed into a 96-well laboratory dish and shipped to the requesting scientist. Using the library, colleagues have found leads to diseases ranging from cancer to HIV.

Meanwhile, Sullivan recently took part in an even more ambitious screening project. This time Sullivan and a multidisciplinary team began with almost 310,000 compounds—a wide net that included known drugs but also thousands of trial compounds that companies had produced but that had not yet demonstrated any therapeutic use. That study, which the team reported in the May 20, 2010, issue of Nature, identified many promising leads for fighting malaria, says Sullivan, not necessarily drugs but chemical "scaffolds" that may help steer researchers toward the drug structures most likely to defeat the parasite.

Best of Both?

The research strategies taken by Sullivan and Bosch could not be more different. But it's possible that their scientific paths may converge at some point.

While Bosch continues to spend most of his time deducing crystal structures, he has also recently begun to take an interest in drug and chemical collections of the sort that Sullivan uses. This interest began when Bosch read a Nature article by scientists who had screened a GlaxoSmithKline chemical compound library that contains 2 million chemicals. They found several thousand that showed some ability to inhibit Plasmodium growth.

When Bosch looked closely at the results, he became excited. Some of the compounds appeared to strike Plasmodium's invasion machinery—direct hits to the proteins whose structures he had studied so closely. Bosch immediately emailed the researchers and asked them to send him samples of their compounds.

None of the chemicals is ready to serve as a malaria drug, says Bosch. They inhibit Plasmodium, but only weakly. But the structure of those chemicals could help him improve the potency of his own drug candidates.

Bosch is also planning to use the Johns Hopkins Clinical Compound Library to search for agents that might bind to aldolase or other parts of the Plasmodium invasion machinery.

"We'll run through them and see if any might potentially hit," he says.


This forum is closed
  • Khan Askar

    Pakistan 04/29/2011 11:11:16 AM

    Very excellent innovative article.

  • Kimberley Hyunji Kim Williams

    GB 04/29/2011 03:29:52 PM

    Go for it! You are aware of the odds and also of the chances as well. There should be more of people pursuing this approach in the field. It might help further if you looked up the existing/earlier works done in a similar fashion, in other fields, for instance channelopathies, other than antimalarials. If you are already fully aware, please kindly accept my apologies for that matter. Good work indeed and wish you more success to come.

    Best wishes, Kimberley

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