Targeting Plasmodium falciparum Phosphatidylinositol Kinases to Develop Next Generation Artemisinin Combination Therapies
Roepe, Paul D
Resistance to WHO mandated front-line antimalarial Artemisinin (ART) combination therapies (ACTs) is a pressing issue. Several synthetic endoperoxides have recently been proposed as superior to ART-based parent drugs traditionally used in ACTs. In 2013, Witkowski et al. developed the ring-stage susceptibility assay (RSA) to measure evolving artemisinin resistance (ARTR). This method was modified to investigate novel endoperoxide drugs. Of the seven compounds tested, synthetic endoperoxide OZ439 was found to be the only compound equipotent vs ARTS and ARTR malarial parasites.Previous efforts to develop ACTs did not consider partner drug mechanism of action (MOA), rather, they were formulated based on drugs available at the time, several of which were primarily used as monotherapy. Surprisingly, resistance to several of these ACT “partner drugs” is now spreading. Going forward, it is crucial to investigate partner drugs with novel MOAs and that pair two compounds that target different molecular pathways in malaria parasites or ACTs that target the same pathway in different ways. This will ensure that parasites will be killed quickly without development of additional resistance. Since ARTs possibly target hundreds of proteins in the parasite and cause parasite death through non-specific oxidative damage, it is important to investigate partner drugs that can target known essential proteins. Previous studies in the Roepe lab showed that PI3K and PI4K inhibitors are potent antimalarials and that the putative targeted enzymes are essential for parasite growth. Therefore, these compounds were investigated as potential partner drugs for next generation ACTs. Both cytostatic and cytocidal activities were studied. The results obtained from these various experiments show that a) PI3K inhibitors make excellent ACT partner drugs, b) PI3K inhibitors can target ARTR strains, c) there is a distinct autophagy pathway in P. falciparum which is inhibited by PI3K inhibitors, d) the autophagy pathway is dysregulated in ARTR parasite strains and e) P. falciparum parasites do not easily develop resistance to PI3K inhibitors in a laboratory setting. I propose that OZ439+PI3K inhibitors are valuable “next generation” ACTs.
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