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Ozonide Antimalarials Alkylate Heme in the Malaria Parasite Plasmodium falciparum.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2019-12-02 , DOI: 10.1021/acsinfecdis.9b00257 Carlo Giannangelo 1 , Dovile Anderson 1 , Xiaofang Wang 2 , Jonathan L Vennerstrom 2 , Susan A Charman 3 , Darren J Creek 1
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2019-12-02 , DOI: 10.1021/acsinfecdis.9b00257 Carlo Giannangelo 1 , Dovile Anderson 1 , Xiaofang Wang 2 , Jonathan L Vennerstrom 2 , Susan A Charman 3 , Darren J Creek 1
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The mechanism of action of ozonide antimalarials involves activation by intraparasitic iron and the formation of highly reactive carbon-centered radicals that alkylate malaria parasite proteins. Given free intraparasitic heme is generally thought to be the iron source responsible for ozonide activation and its likely close proximity to the activated drug, we investigated heme as a possible molecular target of the ozonides. Using an extraction method optimized for solubilization of free heme, untargeted LC-MS analysis of ozonide-treated parasites identified several regioisomers of ozonide-alkylated heme, which resulted from covalent modification of the heme porphyrin ring by an ozonide-derived carbon-centered radical. In addition to the intact alkylated heme adduct, putative ozonide-alkylated heme degradation products were also detected. This study directly demonstrates ozonide modification of heme within the malaria parasite Plasmodium falciparum, revealing that this process may be important for the biological activity of ozonide antimalarials.
中文翻译：
疟原虫恶性疟原虫中的Ozonide抗疟疾烷基化血红素。
臭氧化物抗疟药的作用机制涉及寄生虫内铁的激活和形成以疟疾寄生虫蛋白烷基化的高反应性碳中心自由基。鉴于游离寄生血红素通常被认为是导致臭氧化物活化的铁源，并且可能与活化药物非常接近，因此我们将血红素作为臭氧化物的可能分子靶标进行了研究。使用针对游离血红素溶解进行了优化的提取方法，对臭氧处理过的寄生虫进行的非定向LC-MS分析确定了几种臭氧化烷基化血红素的区域异构体，这是由于臭氧化物衍生自碳中心的自由基对血红素卟啉环进行了共价修饰。除了完整的烷基化血红素加合物外，还检测到了假定的臭氧化物-烷基化血红素降解产物。恶性疟原虫，表明该过程对于臭氧化物类抗疟药的生物活性可能很重要。
更新日期：2019-12-02
中文翻译：
疟原虫恶性疟原虫中的Ozonide抗疟疾烷基化血红素。
臭氧化物抗疟药的作用机制涉及寄生虫内铁的激活和形成以疟疾寄生虫蛋白烷基化的高反应性碳中心自由基。鉴于游离寄生血红素通常被认为是导致臭氧化物活化的铁源，并且可能与活化药物非常接近，因此我们将血红素作为臭氧化物的可能分子靶标进行了研究。使用针对游离血红素溶解进行了优化的提取方法，对臭氧处理过的寄生虫进行的非定向LC-MS分析确定了几种臭氧化烷基化血红素的区域异构体，这是由于臭氧化物衍生自碳中心的自由基对血红素卟啉环进行了共价修饰。除了完整的烷基化血红素加合物外，还检测到了假定的臭氧化物-烷基化血红素降解产物。恶性疟原虫，表明该过程对于臭氧化物类抗疟药的生物活性可能很重要。
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