Identification of an antimalarial synthetic trioxolane drug development candidate
Identification of an antimalarial synthetic trioxolane drug development candidate
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DOI：
10.1038/nature02779
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发表时间：
2004-08-19
期刊：
影响因子：
64.8
通讯作者：
Charman, WN
中科院分区：
文献类型：
--
作者：
Vennerstrom, JL;Arbe-Barnes, S;Charman, WN
30多年前青蒿素的发现提供了一种全新的抗疟结构原型;即在独特的1，2，4-三恶烷杂环中具有药效过氧键的分子（1）。现有证据（2-4）表明，青蒿素和相关的过氧化物抗疟药在被血红素还原激活后发挥杀寄生虫活性，血红素是引起疟疾的寄生虫消化血红蛋白后释放的。这种不可逆的氧化还原反应产生以碳为中心的自由基，导致血红素（5）和蛋白质（酶）6的烷基化，其中之一-肌质-内质网ATP酶PfATP 6（参考文献7）-可能对寄生虫的生存至关重要。值得注意的是，没有证据表明对青蒿素家族药物的任何成员产生耐药性（8）。疟疾的化疗大大受益于半合成青蒿素蒿甲醚和青蒿琥酯，因为它们迅速减少寄生虫负担，具有良好的治疗指数，并提供成功的治疗结果（9）。然而，作为一种药物类别，青蒿素受到化学（10）（半合成可用性、纯度和成本）、生物制药（11）（生物利用度差和有限的药代动力学）和治疗（8，11）（不遵守长期治疗方案和复发）问题的影响，这些问题限制了其治疗潜力。在这里，我们描述了如何合成过氧化物抗疟药物开发候选人被确定在一个合作的药物发现项目。
The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle(1). Available evidence(2-4) suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem(5) and proteins ( enzymes) 6, one of which-the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)-may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs(8). The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes(9). However, as a drug class, the artemisinins suffer from chemical(10) ( semisynthetic availability, purity and cost), biopharmaceutical(11) (poor bioavailability and limiting pharmacokinetics) and treatment(8,11) (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.