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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Combating multi-drug resistant malaria parasite by inhibiting falcipain-2 and heme-polymerization: Artemisinin-peptidyl vinyl phosphonate hybrid molecules as new antimalarials
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Combating multi-drug resistant malaria parasite by inhibiting falcipain-2 and heme-polymerization: Artemisinin-peptidyl vinyl phosphonate hybrid molecules as new antimalarials

机译：通过抑制Falcipain-2和血红素聚合来对抗多药物抗性疟疾寄生虫：阿尔胺蛋白 - 肽基磺酸膦酸杂种分子作为新的抗疟药

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摘要

Artemisinin-based combination therapies (ACTs) have been able to reduce the clinical and pathological malaria cases in endemic areas around the globe. However, recent reports have shown a progressive decline in malaria parasite clearance in South-east Asia after ACT treatment, thus envisaging a need for new artemisinin (ART) derivatives and combinations. To address the emergence of drug resistance to current antimalarials, here we report the synthesis of artemisinin-peptidyl vinyl phosphonate hybrid molecules that show superior efficacy than artemisinin alone against chloroquine-resistant as well as multidrug-resistant Plasmodium falciparum strains with EC50 in pico-molar ranges. Further, the compounds effectively inhibited the survival of ring-stage parasite for laboratory-adapted artemisinin-resistant parasite lines as compared to artemisinin. These hybrid molecules showed complete parasite clearance in vivo using P. berghei mouse malaria model in comparison to artemisinin alone. Studies on the mode of action of hybrid molecules suggested that these artemisinin-peptidyl vinyl phosphonate hybrid molecules possessed dual activities: inhibited falcipain-2 (FP-2) activity, a P. falciparum cysteine protease involved in hemoglobin degradation, and also blocked the hemozoin formation in the food-vacuole, a step earlier shown to be blocked by artemisinin. Since these hybrid molecules blocked multiple steps of a pathway and showed synergistic efficacies, we believe that these lead compounds can be developed as effective antimalarials to prevent the spread of resistance to current antimalarials. (C) 2021 Published by Elsevier Masson SAS.
机译：基于青蒿素的联合疗法（ACT）已经能够减少全球流行地区的临床和病理疟疾病例。然而，最近的报告显示，在ACT治疗后，东南亚的疟疾寄生虫清除率逐渐下降，因此设想需要新的青蒿素衍生物和组合。为了解决目前抗疟药物耐药性的出现，我们在这里报道了青蒿素-肽基-乙烯基膦酸盐杂化分子的合成，该杂化分子对EC50在皮摩尔范围内的氯喹耐药和多药耐药恶性疟原虫菌株的疗效优于青蒿素单用。此外，与青蒿素相比，这些化合物有效地抑制了实验室适应的青蒿素抗性寄生虫株的环期寄生虫存活。与单独使用青蒿素相比，使用伯氏疟原虫小鼠疟疾模型，这些杂交分子在体内显示出完全的寄生虫清除。对杂交分子作用模式的研究表明，这些青蒿素-肽基-乙烯基膦酸盐杂交分子具有双重活性：抑制恶性疟原虫-2（FP-2）活性，一种参与血红蛋白降解的恶性疟原虫半胱氨酸蛋白酶，并阻断食物液泡中的血红素形成，这一步骤之前已被青蒿素阻断。由于这些杂交分子阻断了一条途径的多个步骤，并显示出协同效应，我们相信这些先导化合物可以被开发为有效的抗疟药物，以防止对现有抗疟药物的耐药性传播。（c）2021由爱思唯尔马松SAS出版。

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