Profiling of the anti-malarial drug candidate SC83288 against artemisinins in Plasmodium falciparum

Abstract

Background: The 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.

Results: Based 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.

Conclusion: The 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.

Keywords: Anti-malarial drug; Artemisinin; Artemisinin-based combination therapy; Drug development; Plasmodium falciparum; Resistance; Severe malaria.

Fig. 1

Structures of various antiplasmodial compounds. a artemisinin, b dihydroartemisinin, c artesunate, and d SC83288

Fig. 2

Susceptibility of different P. falciparum strains to SC83288 and dihydroartemisinin. a and b Growth inhibition of NF54 and the artemisinin resistant derivative NF54^ART carrying the PfK13 C580Y mutation by artemisinin (a) and SC83288 (b) in a standard cell proliferation assay with an exposure time of 72 h. c and d Growth inhibition of Dd2 and the SC83288 resistant derivative Dd2^SC by artemisinin (c) and SC83288 (d). Mean ± SEM of 6–13 independent determinations

Fig. 3

Ring stage susceptibility of different P. falciparum strains to dihydroartemisinin and SC83288. a Ring survival assay (RSA) scores of NF54, NF54^ART, Dd2, and Dd2^SC to dihydroartemisinin (DHA). b RSA scores to SC83288. Mean ± SEM of 3–6 independent determinations. Statistical significance was evaluated using the one way ANOVA Holm-Sidak test. ***p < 0.001; n.s. not significant

Fig. 4

Indifferent interaction between artemisinin and SC83288. The fractional half-maximal inhibitory concentrations (FIC₅₀) of artemisinin and SC83288 in the P. falciparum strain Dd2 were displayed in an isobologram. A linear regression was fitted to the data points. Mean ± SEM of 7 independent determinations

Fig. 5

IC₅₀-based relative speed of action profiles of SC83288, artemisinin, and atovaquone. The IC₅₀ values of artemisinin, atovaquone and SC83288 were determined at exposure times of 24, 48 and 72 h in the P. falciparum Dd2 strain [56]. The data are shown normalized to the value obtained at the 72 h time point. Mean ± SEM of 6 independent determinations. Statistical significance was evaluated using the one way ANOVA Holm-Sidak test. ***p < 0.001; n.s. not significant

Fig. 6

Killing rate profile for artesunate, SC83288, atovaquone, alone and in combination. Asynchronous cultures of Dd2 were exposed to 10-times the IC₅₀ concentration of SC82388, artesunate, or atovaquone, alone or in combination, for a duration of 8, 14, 24, 48 or 72 h before the number of re-invading parasites were determined as an indicator of parasite viability. Data were normalized to untreated controls analysed in parallel. Mean ± SEM of four independent determinations