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.

Nature Communications1区 · 综合性期刊

Erratum: SC83288 is a clinical development candidate for the treatment of severe malaria

1区 · 综合性期刊

ArticleOA

作者: Vial, Henri J. ; Lucantoni, Leonardo ; Avery, Vicky M. ; Duffey, Maëlle ; Mazier, Dominique ; Otto, Thomas D. ; Strobl, Stefan ; Fehler, Stefanie K. ; Rösemann, Roman ; Pegoraro, Stefano ; Lanzer, Michael ; Baumgartner, Roland ; Wang, Yulin ; Moreno-Sabater, Alicia ; Sanchez, Cecilia P.

Nature Communications 8 Article number:14193 (2017); Published 31 January 2017; Updated 6 Apr 2017 This Article contains errors in Figs. 1 and 8 that were introduced during the production process. The compound on the lower right side of Fig. 1 is labelled incorrectly and should be labelled ‘SC83288’. The correct version of Fig.

Nature Communications1区 · 综合性期刊

SC83288 is a clinical development candidate for the treatment of severe malaria

1区 · 综合性期刊

ArticleOA

作者: Otto, Thomas D ; Duffey, Maëlle ; Wang, Yulin ; Vial, Henri J ; Strobl, Stefan ; Fehler, Stefanie K ; Lanzer, Michael ; Rösemann, Roman ; Mazier, Dominique ; Pegoraro, Stefano ; Lucantoni, Leonardo ; Baumgartner, Roland ; Avery, Vicky M ; Moreno-Sabater, Alicia ; Sanchez, Cecilia P

AbstractSevere malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca2+ transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria.

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