MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis.
MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis.
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米皮剂：靶向类异丙生素生物合成的有效抗疟药。
DOI：
10.1038/s41598-017-07159-y
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发表时间：
2017-08-21
影响因子：
4.6
通讯作者：
John ARO
中科院分区：
文献类型：
--
作者：
Edwards RL;Brothers RC;Wang X;Maron MI;Ziniel PD;Tsang PS;Kraft TE;Hruz PW;Williamson KC;Dowd CS;John ARO
恶性疟原虫对一线治疗药物耐药的出现促使人们努力鉴定和验证具有新作用机制的药物。MEPicides代表了一类新的抗疟药，其抑制类异戊二烯生物合成的磷酸甲脂酶（MEP）途径的酶，包括临床验证的靶标，磷酸脱氧木酮糖还原异构酶（Dxr）。在这里，我们描述了RCB-185，一种亲脂性前药，对无性寄生虫具有纳摩尔活性。用RCB-185处理的恶性疟原虫的生长通过类异戊二烯前体补充来挽救，并且处理显著降低了Dxr酶下游的代谢物水平。此外，产生较高水平Dxr底物的寄生虫对RCB-185具有抗性。值得注意的是，对当前疗法具有抗性的环境分离株对RCB-185仍然敏感，该化合物有效地治疗了性寄生虫，并且在疟疾感染的小鼠中既安全又有效。总的来说，我们的数据表明，RCB-185有效地和选择性地抑制恶性疟原虫中的Dxr，并且代表了用于进一步药物开发的有希望的先导化合物。
The emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme. In addition, parasites that produced higher levels of the Dxr substrate were resistant to RCB-185. Notably, environmental isolates resistant to current therapies remained sensitive to RCB-185, the compound effectively treated sexually-committed parasites, and was both safe and efficacious in malaria-infected mice. Collectively, our data demonstrate that RCB-185 potently and selectively inhibits Dxr in P. falciparum, and represents a promising lead compound for further drug development.
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影响因子：
2.7
作者：
Jackson, Emily R.;San Jose, Geraldine;Brothers, Robert C.;Edelstein, Emma K.;Sheldon, Zachary;Haymond, Amanda;Johny, Chinchu;Boshoff, Helena I.;Couch, Robin D.;Dowd, Cynthia S.
通讯作者：
Dowd, Cynthia S.
影响因子：
5.2
作者：
Imlay, Leah;Odom, Audrey R
通讯作者：
Odom, Audrey R
影响因子：
4.8
作者：
Cassera, MB;Gozzo, FC;Katzin, AM
通讯作者：
Katzin, AM
DOI：
10.4269/ajtmh.2004.70.119
发表时间：
2004-02-01
影响因子：
3.3
作者：
Corbett, Y;Herrera, L;Ortega-Barria, E
通讯作者：
Ortega-Barria, E
影响因子：
4.8
作者：
Henriksson, Lena M.;Unge, Torsten;Jones, T. Alwyn
通讯作者：
Jones, T. Alwyn