Nardella Flore, Halby Ludovic, Hammam Elie, Erdmann Diane, Cadet-Daniel Véronique, Peronet Roger, Ménard Didier, Witkowski Benoit, Mecheri Salah, Scherf Artur, Arimondo Paola B
Unité Biologie des Interactions Hôte-Parasite, Département de Parasites et Insectes Vecteurs, Institut Pasteur, CNRS ERL 9195, INSERM Unit U1201, 25-28 Rue du Dr Roux, Paris 75015, France.
Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, UMR n°3523, CNRS, 28 Rue du Dr Roux, Paris 75015, France.
ACS Cent Sci. 2020 Jan 22;6(1):16-21. doi: 10.1021/acscentsci.9b00874. Epub 2019 Nov 27.
Malaria is the deadliest parasitic disease affecting over 200 million people worldwide. The increasing number of treatment failures due to multi-drug-resistant parasites in South-East Asia hinders the efforts for elimination. It is thus urgent to develop new antimalarials to contain these resistant parasites. Based on a previous report showing the presence of DNA methylation in , we generated new types of DNA methylation inhibitors against malaria parasites. The quinoline-quinazoline-based inhibitors kill parasites, including artemisinin-resistant field isolates adapted to culture, in the low nanomolar range. The compounds target all stages of the asexual cycle, including early rings, during a 6 h treatment period; they reduce DNA methylation in the parasite and show activity at 10 mg/kg. These potent inhibitors are a new starting point to develop fast-acting antimalarials that could be used in combination with artemisinins.
疟疾是影响全球超过2亿人的最致命寄生虫病。东南亚地区因多重耐药寄生虫导致的治疗失败病例不断增加，阻碍了疟疾消除工作。因此，迫切需要开发新的抗疟药物来控制这些耐药寄生虫。基于之前一份显示疟原虫存在DNA甲基化的报告，我们研发了新型针对疟原虫的DNA甲基化抑制剂。基于喹啉 - 喹唑啉的抑制剂能在低纳摩尔浓度范围内杀死疟原虫，包括适应培养的耐青蒿素野外分离株。在6小时的治疗期间，这些化合物靶向无性生殖周期的所有阶段，包括早期环状体；它们可降低疟原虫中的DNA甲基化，并在10毫克/千克时显示出活性。这些强效抑制剂是开发可与青蒿素联合使用的速效抗疟药物的新起点。
