1. Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins
- Author
-
Eric Hanssen, Nectarios Klonis, María del Pilar Crespo, Silvia Teguh, Con Dogovski, Francis C. K. Chiu, Susan A. Charman, Steven Batinovic, Stanley C. Xie, Tuo Yang, Che A. Stafford, and Leann Tilley
- Subjects
Artemisinins ,Plasmodium ,Proteolysis ,Resistance ,Plasmodium falciparum ,Drug Evaluation, Preclinical ,Drug Resistance ,Protozoan Proteins ,Biology ,Cysteine Proteinase Inhibitors ,Toxicology ,Lethal Dose 50 ,03 medical and health sciences ,chemistry.chemical_compound ,Antimalarials ,Hemoglobins ,Chloroquine ,Leucine ,parasitic diseases ,medicine ,Humans ,Artemisinin ,Malaria, Falciparum ,Heme ,030304 developmental biology ,0303 health sciences ,medicine.diagnostic_test ,030306 microbiology ,Falcipains ,Drug Synergism ,Cell Biology ,biology.organism_classification ,Haemoglobin degradation ,Cysteine protease ,3. Good health ,Malaria ,Cysteine Endopeptidases ,Biochemistry ,chemistry ,medicine.drug ,Research Article - Abstract
Current first-line artemisinin antimalarials are threatened by the emergence of resistant Plasmodium falciparum. Decreased sensitivity is evident in the initial (early ring) stage of intraerythrocytic development, meaning that it is crucial to understand the action of artemisinins at this stage. Here, we examined the roles of iron (Fe) ions and haem in artemisinin activation in early rings using Fe ion chelators and a specific haemoglobinase inhibitor (E64d). Quantitative modelling of the antagonism accounted for its complex dependence on the chemical features of the artemisinins and on the drug exposure time, and showed that almost all artemisinin activity in early rings (>80%) is due to haem-mediated activation. The surprising implication that haemoglobin uptake and digestion is active in early rings is supported by identification of active haemoglobinases (falcipains) at this stage. Genetic down-modulation of the expression of the two main cysteine protease haemoglobinases, falcipains 2 and 3, renders early ring stage parasites resistant to artemisinins. This confirms the important role of haemoglobin-degrading falcipains in artemisinin activation, and shows that changes in the rate of artemisinin activation could mediate high-level artemisinin resistance., Summary: Down-modulation of the expression of haemoglobin-degrading falcipains in P. falciparum renders early ring stage parasites resistant to artemisinins.
- Published
- 2016