Access: Parasites Lost




Still, it's quite a leap from carbon monoxide to malaria. "It was totally fortuitous that we got into this area. We're interested in NMR, proteins, and quantum chemistry," Oldfield says now. He knew Urbina from their days in the United Kingdom and at the Massachusetts Institute of Technology. His NMR work suggested a useful collaboration with Urbina, who was visiting from Caracas, and they were joined by local parasitology experts Docampo and Moreno.

As they studied the chemistry of parasitic protozoa using NMR spectroscopy, they observed copious quantities of several compounds, including inorganic diphosphate and triphosphate, in the little pockets, or vacuoles, of all the major pathogens. This led to the idea that parasite growth might be inhibited in the presence of a stable analog of diphosphate. One such stable analog is nitrogen-containing bisphosphonate. The researchers were particularly attracted to bisphosphonates because they are already marketed to treat osteoporosis and other bone diseases.

Trypanosoma cruzi, the parasite that causes Chagas' disease, in the blood. Photo courtesy of Sinclair Stammers for the World Health Organization Special Programme for Research and Training in Tropical Diseases.

Their bench science confirmed that bisphosphonates are indeed potent inhibitors of the organisms that cause malaria, as well as the less-common diseases of African sleeping sickness, Chagas' disease, visceral leishmaniasis, and toxoplasmosis. The protozoa that cause encephalitis and diarrhea in patients, such as those with AIDS, who have comprimised immune systems also appear inhibited by bisphosphonate in the lab.


		Leishmania donovani, the cause of leishmaniasis, in live culture. Photo courtesy of Sinclair Stammers for the World Health Organization Special Programme for Research and Training in Tropical Diseases.

To further explore precisely how bisphosphonates kill parasites, the Oldfield group proposed that the production of one phosphate compound in particular—farnesyl pyrophosphate or FPP—was being inhibited. FPP plays a central role in metabolism in a biochemical cascade known as the isoprene pathway, and the structures of the bisphosphonate drugs were proposed to be akin to those of a precursor to FPP.

So the group turned to Gaussian 98's quantum chemical calculations of the drugs' electronic structure and molecular geometries. From their results, they proposed how bisphosphonates interfere with the formation of FPP, which cells use to make sterols (as in cholesterol or ergosterol), and the signaling molecules cells use to communicate with each other. Working with tropical disease parasites in London, Croft was able to confirm that the drug target is the protein that makes FPP. Interestingly, the same target has been identified by other research groups studying the therapeutic mechanism of bisphosphonates in osteoporosis and bone disease, Oldfield says. Using NCSA's Origin2000, the researchers can now accurately predict the activity of their bisphosphonate drug molecules.