AI Summary
Structural insights on a new antimalarial drug candidate's interaction with the malaria parasite Plasmodium falciparum have been discovered, leading to the development of potential therapies for drug-resistant malaria. The study used cryo-electron microscopy to show how the drug binds to its target and revealed the effects of mutation on the parasite's sensitivity. These findings support the development of new antimalarials that are less susceptible to resistance.
Structural insights into a potent antimalarial drug candidate’s interaction with the malaria parasite Plasmodium falciparum have paved the way for drug-resistant malaria therapies, according to a new study by researchers at Weill Cornell Medicine and Van Andel Institute.
The antimalarial molecule, TDI-8304, is one of a new class of experimental therapeutics that targets the proteasome, an essential, multiprotein complex in P. falciparum cells. Two years ago, the researchers showed in a preclinical study that TDI-8304 potently kills malaria parasites at multiple stages of their life cycle and clears parasites in animal model of malarial infection.
In the new study, published Dec. 14 in Nature Communications, the researchers used cryo-electron microscopy (cryo-EM) to show how TDI-8304 fastens to its proteasome target. The high-resolution imaging also revealed what happens to P. falciparum, the major cause of malaria deaths, when it mutates to become less sensitive to TDI-8304.
This study gives us insights that should help in the development of new proteasome-inhibitor antimalarials that are not very susceptible to resistance.”
Dr. Gang Lin, study co-senior author, associate professor of research in microbiology and immunology at Weill Cornell Medicine
“Remarkably, the mutation that makes P. falciparum less sensitive to TDI-8304 makes it more sensitive to compounds that target a different part of the parasite proteasome,” said co-senior author Dr. Huilin Li, professor and chair of the Department of Structural Biology at Van Andel Institute. “Our cryo-EM analysis illuminated how that ‘collateral sensitivity’ occurs.”
The study’s first author was Dr. Hao-Chi