Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany.
German Center for Infection Research (DZIF), Partner Site Heidelberg, 69120, Heidelberg, Germany.
Malar J. 2018 Mar 20;17(1):121. doi: 10.1186/s12936-018-2279-4.
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.
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.
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.
人类疟原虫恶性疟原虫对目前使用的药物的耐药性不断增加，迫切需要开发新的抗疟药物。特别是，如果临床耐药性增加到一线青蒿素联合疗法，应努力开发快速作用的抗疟化合物。SC83288 是一种阿米卡林衍生物，是治疗严重疟疾的临床开发候选药物。SC83288 作用迅速，能够以低纳摩尔浓度在体外清除恶性疟原虫寄生虫，并在体内人源化 SCID 小鼠模型系统中清除。在这项研究中，对 SC83288 抗疟原虫活性进行了分析，以评估其替代或与青蒿素衍生物联合应用的潜力。
基于生长抑制和环存活测定，在用对这些药物之一耐药的寄生虫系中，未观察到青蒿素和 SC83288 之间的交叉耐药性。此外，两种药物之间未观察到协同或拮抗相互作用。这项研究进一步证实，SC83288 是几种独立测定中的一种快速作用药物。SC83288 和青蒿琥酯的组合保持了两种成分的快速寄生虫杀伤活性。
本研究结果与青蒿素和 SC83288 具有不同的作用模式和不同的耐药机制一致。这项研究进一步支持继续开发 SC83288 用于严重疟疾的临床开发，作为青蒿素耐药地区青蒿素的替代药物。考虑到其快速的抗疟活性，SC83288 可以与一种作用缓慢的抗疟药物联合使用。
