Ismail Hanafy M, Barton Victoria E, Panchana Matthew, Charoensutthivarakul Sitthivut, Biagini Giancarlo A, Ward Stephen A, O'Neill Paul M
Research Centre for Drugs and Diagnostics Liverpool School of Tropical Medicine Pembroke Place Liverpool L3 5QA UK.
Department of Chemistry University of Liverpool Liverpool L69 7ZD UK.
Angew Chem Weinheim Bergstr Ger. 2016 May 23;128(22):6511-6515. doi: 10.1002/ange.201512062. Epub 2016 Apr 18.
In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross-resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based protein-profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi-quantitatively, suggesting a common mechanism of action that raises concerns about potential cross-resistance liabilities.
尽管最近正在研发的内过氧化物抗疟药有所增加，但目前尚不清楚所有这些化学类型是否具有共同的作用机制。这一点很重要，因为它会影响不同类别之间的交叉耐药风险。在这里，我们使用新型的基于可点击1,2,4 - 三氧杂环戊烷活性的蛋白质谱分析探针（ABPPs）来研究这一命题。具有强大抗疟活性的ABPPs能够在恶性疟原虫（3D7）的无性红细胞期对蛋白质靶点进行烷基化。重要的是，将烷基化指纹图谱与青蒿素等效ABPPs产生的图谱进行比较，证实了高度保守的烷基化谱，两种内过氧化物类别均靶向参与糖酵解、血红蛋白降解、抗氧化防御、蛋白质合成和蛋白质应激途径的蛋白质，这些都是疟原虫生存所必需的生物学过程。两种化学类型的烷基化特征在定性和半定量方面都显示出显著重叠（约90%），这表明存在共同的作用机制，这引发了对潜在交叉耐药问题的担忧。
