Abstract
BackgroundThe increased resistance of the human malaria parasite Plasmodium falciparum to currently employed drugs creates an urgent call for novel anti-malarial drugs. Particularly, efforts should be devoted to developing fast-acting anti-malarial compounds in case clinical resistance increases to the first-line artemisinin-based combination therapy. SC83288, an amicarbalide derivative, is a clinical development candidate for the treatment of severe malaria. SC83288 is fast-acting and able to clear P. falciparum parasites at low nanomolar concentrations in vitro, as well as in a humanized SCID mouse model system in vivo. In this study, the antiplasmodial activity of SC83288 against artemisinins was profiled in order to assess its potential to replace, or be combined with, artemisinin derivatives.ResultsBased on growth inhibition and ring survival assays, no cross-resistance was observed between artemisinins and SC83288, using parasite lines that were resistant to either one of these drugs. In addition, no synergistic or antagonistic interaction was observed between the two drugs. This study further confirmed that SC83288 is a fast acting drug in several independent assays. Combinations of SC83288 and artesunate maintained the rapid parasite killing activities of both components.ConclusionThe results obtained in this study are consistent with artemisinins and SC83288 having distinct modes of action and different mechanisms of resistance. This study further supports efforts to continue the clinical development of SC83288 against severe malaria as an alternative to artemisinins in areas critically affected by artemisinin-resistance. Considering its fast antiplasmodial activity, SC83288 could be combined with a slow-acting anti-malarial drug.
Highlights
The increased resistance of the human malaria parasite Plasmodium falciparum to currently employed drugs creates an urgent call for novel anti-malarial drugs
The ring survival assay (RSA) takes into account the antiplasmodial activity of artemisinin and its derivatives against the early blood stages [36, 52]
Four different strains of P. falciparum were used in these assays: the artemisinin and SC83288 sensitive P. falciparum strains NF54 and Dd2, the genetically engineered artemisinin-resistant NF54 mutant line bearing a mutation in the kelch 13 gene (PfK13 C580Y), an established marker of artemisinin resistance [52], and a Dd2 derived SC83288 resistant line [20]
Summary
The increased resistance of the human malaria parasite Plasmodium falciparum to currently employed drugs creates an urgent call for novel anti-malarial drugs. Efforts should be devoted to developing fastacting anti-malarial compounds in case clinical resistance increases to the first-line artemisinin-based combination therapy. SC83288, an amicarbalide derivative, is a clinical development candidate for the treatment of severe malaria. SC83288 is fast-acting and able to clear P. falciparum parasites at low nanomolar concentrations in vitro, as well as in a humanized SCID mouse model system in vivo. SC83288, an amicarbalide derivative, is active against P. falciparum blood stages at low nanomolar concentrations in vitro, with IC50 values of 3 nM. SC83288 is able to clear a P. falciparum infection in a humanized NOD/SCID mouse model system within 48 h following intraperitoneal injections of 2.5 mg kg−1 once per day over a period of 3 days [20]. PfATP6 does not seem to be the molecular target of SC83288 but rather a component of resistance [20]
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