Project Lead(s): Thanat Chookajorn
Between 2000 and 2015, the number of new cases of malaria fell globally by 37% and in Africa by 42%.
Malaria remains one of the most devastating infectious diseases in the world, with Plasmodium falciparum being the deadliest form of the malaria parasite.
Artemisinin Combination Therapies (ACTs) are currently the front-line treatments against P. falciparum malaria but there is serious concern that malaria parasites are once again developing widespread resistance to this vital treatment.
The objective of this project was to reverse the course of drug-resistant evolution, making drug-resistant malaria parasites drug-sensitive again through targeting fitness loss during the gain of malaria drug resistance.
It is well known that there is trade-off between gain of drug resistance and loss in fitness during the evolutionary course toward drug resistance.
Fitness trade-off results in weak parasites that require compensatory measures to survive.
For antifolate resistance, the gain of drug-resistant mutations at the gene encoding dihydrofolate reductase (DHFR), the target of antifolate pyrimethamine, impose fitness loss. The parasites compensate for fitness loss by acquiring extra copies of the gene encoding GTP cyclohydrolase I, the rate-limiting upstream enzyme of the folate pathway.
The increase in GCH1 amount allows the parasites to quickly develop pyrimethamine resistance.
The team sought to inhibit the function of GCH1 by using compounds to interfere with pyrimethamine resistance evolution.
They developed a plate-format GCH1 inhibition assay and identified compounds with antimalarial activities in the nanomolar range that can interfere with the function of GCH1.
They also adopted Encoded Library Technology (ELT) with a nucleotide-tagged library, to select enriched compounds with affinity to GCH1.
At present, long-term selection of putative GCH1 inhibitors is underway to observe whether GCH1 inhibitors can revert parasites with DHFR mutations back to wild-type.
Despite significant challenges, the project successfully showed that artemisinin-resistant malaria parasites are weak and produce fewer progenies.
The team was also successful in developing the assay to test GCH1 inhibitors on DHFR mutation selection.
Studies on fitness trade-off in artemisinin resistance also resulted in a simple and robust assay for identifying artemisinin-resistant parasites.
The challenge for the project remains the SAR (structure-activity relationship) analysis of compounds to improve potency and ligand efficiency.
Scaling the assay will require a clinical study to determine clinical correlation between maturation failure under starvation and artemisinin treatment failure.
The team intends to seek support from Grand Challenges Canada, with a potential working partner on the clinical side being the Mahidol-Oxford Research Unit (MORU), which has several field sites for malaria clinical studies.