A paper published inNaturedescribes how a group of scientists from Stanford University, used cutting-edge technology to design a smarter drug to combat the resistant strain.
"Artemisinin causes damage to the proteins in the malaria parasite that kill the human cell, but the parasite has developed a way to deal with that damage. So new drugs that work against resistant parasites are desperately needed," said the co-author.
The new drug targets the parasite's waste disposal system, known as a proteasome.
"The parasite's proteasome is like a shredder that chews up damaged or used-up proteins. Malaria parasites generate a lot of damaged proteins as they switch from one life stage to another and are very reliant on their proteasome, making it an excellent drug target," the co-author said.
Researchers purified the proteasome from the malaria parasite and examined its activity against hundreds of different peptide sequences using a novel method. Using this information, they designed inhibitors that selectively targeted the parasite proteasome, while sparing the human host enzyme. This high degree of selectivity allowed the team to confirm that the drug could be used to clear parasites from infected mice.
Then, the group at the MRC in Cambridge used a revolutionary new technique called Single Particle Cryo-Electron Microscopy to generate a three-dimensional, high-resolution structure of a protein, based on thousands composite images. This is the first time this technique has been used to design a drug.
Researchers tested the new drug in red blood cells infected with parasites and found that it was as effective at killing the artemisinin resistant parasites as it was for the sensitive parasites.
"The new proteasome inhibitors actually complement artemisinin drugs," the co- author said. "Artemisinins cause protein damage and proteasome inhibitors prevent the repair of protein damage. A combination of the two provides a double whammy and could rescue the artemisinins as anti-malarials, restoring their activity against resistant parasites."
The researchers are collaborating with Takeda Pharmaceuticals to find the proteasome inhibitor drug for human treatment.