LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, Toulouse, France.
MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, Toulouse, France.
J Antimicrob Chemother. 2024 Nov 4;79(11):2877-2886. doi: 10.1093/jac/dkae300.
Ganaplacide, also known as KAF156, is among the new antimalarial drug candidates that have successfully reached Phase III clinical trials, and is proposed in combination with lumefantrine. This combination could replace the current front-line artemisinin-based combination therapies (ACTs) in case of Plasmodium falciparum resistance to both artemisinins and partner drugs. Indeed, the African continent, where the malaria burden is the highest, is currently experiencing worrying multiple emergences and spread of artemisinin resistance, which urges for the exploration of the antiparasitic properties of KAF156 in this context.
The objectives of this work were firstly to evaluate the risk of cross-resistance between artemisinins and KAF156 alone, and in combination with lumefantrine, using a panel of artemisinin-resistant strains carrying different pfk13 mutations and markers of other antiplasmodial drug resistances; secondly to explore in vitro the relevance of combining KAF156 and lumefantrine with artemisinins, based on the model of triple ACTs.
Our results highlighted that KAF156 activity was not impaired by mutations in pfk13, pfcrt, pfmdr1, pfmdr2, pfdhps and pfdhfr genes or by pfmdr1 amplification. Moreover, we demonstrated that KAF156 alone and in combination with lumefantrine was active against artemisinin-resistant parasites, including when they are quiescent.
All these in vitro results evidence that multi-drug resistant parasites currently in circulation in the field might not affect KAF156 efficacy, and are encouraging signs for KAF156 use in a triple ACT to preserve the use of artemisinins for as long as possible.
甘氨双唑钠（Ganaplacide），又名 KAF156，是已成功进入 III 期临床试验的新型抗疟药物候选物之一，拟与青蒿琥酯联合使用。如果恶性疟原虫对青蒿素及其联合用药均产生耐药性，这种联合用药方案可能会替代目前的一线青蒿素为基础的联合疗法（ACT）。事实上，在疟疾负担最高的非洲大陆，青蒿素耐药性的多重出现和传播令人担忧，这促使人们在这种情况下探索 KAF156 的抗寄生虫特性。
本研究的目的首先是使用携带不同 pfk13 突变和其他抗疟药物耐药标记的抗青蒿素株系，评估青蒿素及其与青蒿琥酯联合用药与 KAF156 之间交叉耐药的风险；其次，根据三药 ACTs 模型，探索体外联合使用 KAF156 和青蒿琥酯与青蒿素的相关性。
我们的研究结果表明，KAF156 的活性不受 pfk13、pfcrt、pfmdr1、pfmdr2、pfdhps 和 pfdhfr 基因突变、pfmdr1 扩增的影响。此外，我们还证明了 KAF156 单独使用以及与青蒿琥酯联合使用对青蒿素耐药寄生虫均具有活性，包括处于休眠状态的寄生虫。
所有这些体外结果表明，目前在田间循环的多药耐药寄生虫可能不会影响 KAF156 的疗效，这是 KAF156 用于三药 ACT 以尽可能长时间保留青蒿素使用的令人鼓舞的迹象。
