Drug-resistant malaria is on the rise. Depending on location, Plasmodium falciparum, the parasite that causes malaria, is resistant to nearly all available malaria drugs, and has recently begun to show resistance to artemisinin and artemisinin combination therapies in Southeast Asia. The pressure is on to create new malaria drugs to meet this growing challenge crisis. And public health officials say it’s urgent that these treatments be low in cost.
Now, an international team of researchers is reporting a possible way to resurrect a class of malaria drugs that initially failed in humans. They say this old class of vitamin B5-related compounds is inexpensive and readily available. With a stereochemistry tune-up, they’ve demonstrated a new variation on these compounds that kills drug-resistant P. falciparum. The researchers hope the work could lead to inexpensive new medicines to treat this deadly disease (Sci. Transl. Med. 2019, DOI: 10.1126/scitranslmed.aas9917).
“There are currently good malaria therapies, but as always in infectious disease, resistance is emerging,” says Joost Schalkwijk of Radboud University, who led the research. “For that reason, we need to keep on developing small molecules.”
The team wanted to develop more effective versions of pantothenamides, antimalarial molecules that cannot be used in humans alone because they are rapidly degraded by enzymes called pantetheinases. To improve the molecules’ longevity, the research team changed the stereochemistry, inverting one of the amide bonds in the middle of the molecule. This “flip,” says Schalkwijk, thwarts pantetheinases. Then, they tinkered with the resulting stable intermediate molecule and experimented with adding side chains and other variations they hoped would improve its efficacy at low concentrations.
The most potent candidate, MMV689258, has an aromatic side chain with a fluorine attached. Nanomolar concentrations of the compound kill P. falciparum, even drug resistant strains of the parasite. In mice that carry human blood, one dose of MMV689258 was able to reduce P. falciparum infection by up to 99.9% in seven days.
The transmission of malaria is complicated. When a mosquito feeds on an infected human, it picks up the parasite from the blood of that human. When an infected mosquito feeds on another person, it injects the parasite into that person while it sucks up blood. In the human, the parasite travels to the liver, where it morphs into a different life stage, and then escapes to the blood stream, where it infects and kills red blood cells, leading to one of the clinical symptoms of infection, anemia. Schalkwijk says that their compound blocks P. falciparum from growing in mosquitoes as well as in human blood cells, showing that it can work at different life stages of the parasite.
The team analyzed metabolites to search out MMV689258’s target. They believe it acts on the pathway involved in the formation of coenzyme A, an important metabolic molecule, and that it might be blocking a step in the formation of acetyl CoA.
Schalkwijk says that while a compound like MMV689258 could be used in human trials, they are refining other compounds at the same time using similar chemical steps.
Biochemist Meg Phillips at the University of Texas Southwestern Medical Center says it’s a good thing the group is continuing to refine their possible drug compounds. She says it’s not clear that these new pantothenamides will meet some of the standards set by non-governmental organizations that help carry out malaria drug development. She is skeptical MMV689258 will work when given in a single dose because its predicted half-life in humans seems too short. And it may be vulnerable to P. falciparum’s propensity to develop resistance to antimalarials, because the researchers were able to coax resistant strains out of P. falciparum while exploring the compound’s mechanism.
Still, she says, it’s important to have new drug targets such as the acetyl CoA pathway to work against, and she says she’s curious how the team’s effort will pan out.
“This paper really represents a very excellent example of that early phase where we are identifying a new target,” she says. Now it’s up to the drug discovery pipeline to show if the compound class will work, or if the team will have to refine it even further.