Aix-Marseille University, CNRS, UMR 7273, 13007 Marseille, France.
LCC-CNRS, Laboratoire de Chimie de Coordination and MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, Université de Toulouse, CNRS, 31077 Toulouse, France.
Molecules. 2024 Mar 21;29(6):1397. doi: 10.3390/molecules29061397.
The emergence and spread of drug-resistant parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against . Since the parasite enzymes should trigger the production of the active drug in the parasite's food vacuoles, our approach is summarized as "to dig its grave with its fork". However, despite promising sub-micromolar IC values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity.
耐药寄生虫的出现和传播严重影响了全球疟疾控制,疟疾是死亡率和发病率方面最重要的热带病。这种情况促使我们考虑使用肽-烷氧基胺衍生物作为新型抗疟前药,这些前药可能对治疗耐药疟原虫有效。事实上,前药的肽标签被设计成可被寄生虫消化蛋白酶水解,从而产生高度不稳定的烷氧基胺药物,这些药物会自发、瞬间均裂成两个自由基,其中一个有望对起作用。由于寄生虫酶应该在寄生虫的食物泡中触发活性药物的产生,我们的方法可以概括为“用它的叉子给自己掘墓”。然而,尽管在经典的化学敏感性测定中具有有前景的亚微摩尔 IC 值,更深入的测试表明,这些化合物的抗寄生虫活性可能是由于其细胞抑制活性,而不是真正的抗寄生虫特性,这表明抗疟原虫活性不能仅仅基于测量抗增殖活性。因此,必须通过适当的测试,将真正的杀寄生虫活性与细胞抑制活性区分开来。