Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Department of Pharmacology, School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE UK.
Nat Commun. 2017 May 24;8:15159. doi: 10.1038/ncomms15159.
K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.
疟原虫 K13 基因突变是青蒿素耐药性的主要标志，这威胁到青蒿素为基础的联合疗法的长期临床应用，而青蒿素为基础的联合疗法是现代疟疾治疗的基石。在这里，我们描述了一个跨国药物发现计划，该计划提供了一种基于合成四氧烷的分子 E209，它符合药物发现风险投资公司候选药物概况的关键要求。E209 对体外多种疟原虫和 vivax 株具有强大的纳摩尔抑制活性，在体内啮齿动物模型中对疟原虫有效，产生与双氢青蒿素相当的寄生虫减少率，并且药代动力学和药效学特征与单剂量治愈兼容。用表达 K13 变体形式的转基因寄生虫进行的体外研究显示，与在东南亚主要观察到的 C580Y 突变没有交叉耐药性。E209 是一种具有联合药代动力学和药效学特征的新一代内过氧化物，克服了青蒿素衍生物的缺点。
