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A Double Dose of Hope

Michael Glenwood

A Double Dose of Hope (continued)

Finding the Perfect Fit

Bosch’s first encounter with malaria came when he was a child.

He lived first in South and Central America, and then spent 11 years in Nigeria, where his father worked for a multinational corporation. Malaria was pervasive there, and young Jürgen was struck with the disease several times. Fortunately, he says, “it was always a mild case, like a flu, the same type of symptoms.” He also had access to good health care and medications, he notes, which cleared up his infection in two or three days. Many in Nigeria weren’t so lucky—including the thousands of Nigerian children who succumbed to the disease each year.

A friend of Bosch’s became one such victim. The boy, another member of the ex-pat community, had come down with malaria while on a trip to Germany. “He didn’t come back,” says Bosch. “That’s how we learned.” The boy’s doctors did not recognize the disease until the infection had become severe. By then, it was too late.

“If you want to develop a new drug, you’re going to fail more than 90 percent of the time. That’s the reality of the process.” —David Sullivan

Bosch’s firsthand view of malaria stimulated his interest in tropical diseases; he went on to earn a PhD at the Max Planck Institute in Germany and to specialize in using crystallography to study tropical diseases.

Crystallography is like an art, says Bosch. It also is a skill that comes with its own challenges, number one being constraints imposed by the simple laws of physics: Delicate crystals break easily. Not only that, says Bosch. “Even if you only bend a crystal, you can disrupt its lattice structure.” Growing crystals is also tricky; some require exact temperatures or acidity. And the pace of formation is crucial.

“If a crystal forms too fast, mistakes will happen and the crystal will be more fragile,” says Bosch. All of this, he says, “requires tremendous patience and endurance.”

One recent day in his office, Bosch calls up on his computer screen a brilliantly colored image of a protein called aldolase—a complex protein that Bosch calls part of the Plasmodium’s “invasion machinery,” the molecular apparatus that the parasite uses to enter and invade the liver and red blood cells of its human hosts.

On the screen, aldolase looks something like a lumpy catcher’s mitt. Bosch points to a crevice. “We want a drug that will fit into this crevice and touch this particular area,” he says, pointing. An effective drug would slip into this space the way a baseball flies into the palm of a catcher’s glove. That interaction, Bosch posits, will knock out the parasite’s invasion machinery—and, therefore, prevent Plasmodium from entering a host cell.

Bosch clicks some keys and a green sausage-shaped molecule appears on the screen, seated within the crevice. He has already designed 60 small molecules that he hopes will bind to parts of the invasion machinery, including this one. To examine the extent of binding, he mixes a candidate drug with aldolase or another part of the invasion machinery. He then crystallizes that complex, freezes the crystals and sends them to a synchrotron facility in California. At the facility, X-rays are fired at the crystals, and the diffraction of those beams is used to generate images of the complex’s structure.

“We can see the space in the cavity where the compound binds,” says Bosch. “Then we can ask, do we want to make [the drug] larger, or a different shape? You know which chemical group will fit where and you can rationally make decisions” to build a more effective drug.

It’s an elegant approach. Bosch is not aware of anyone who has ever designed a malaria drug this way. Still, he says, “I’m positive we’ll find something.” In the best-case scenario, that “something” will be a cure. But if not a cure, the experiments, he says, will at least provide new avenues to pursue in the search for a cure.

 

Comments

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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