Diversity-oriented synthesis probe targets Plasmodium falciparum cytochrome b ubiquinone reduction site and synergizes with oxidation site inhibitors.
Diversity-oriented synthesis probe targets Plasmodium falciparum cytochrome b ubiquinone reduction site and synergizes with oxidation site inhibitors.
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以多样性为导向的合成探针靶向恶性疟原虫细胞色素B泛氨酸酮还原位点，并与氧化位点抑制剂协同作用。
DOI：
10.1093/infdis/jiu565
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发表时间：
2015-04-01
期刊：
影响因子：
--
通讯作者：
Wirth DF
中科院分区：
文献类型：
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作者：
Lukens AK;Heidebrecht RW Jr;Mulrooney C;Beaudoin JA;Comer E;Duvall JR;Fitzgerald ME;Masi D;Galinsky K;Scherer CA;Palmer M;Munoz B;Foley M;Schreiber SL;Wiegand RC;Wirth DF
背景：目前抗疟药物耐药性的出现和传播仍然是一个紧迫的问题，这就增加了对具有新作用模式的化合物的需求。 多样性导向合成（DOS）文库弥合了常规小分子和天然产物文库之间的差距，允许在鉴定新型寄生虫途径的探针的努力中询问更多样的化学空间。方法：我们使用全细胞表型分析从DOS文库中筛选和优化探针。 采用抗性选择和全基因组测序方法来鉴定化合物的细胞靶点。结果：我们鉴定了一种新的具有纳摩尔效力的恶性疟原虫大环抑制剂，并鉴定了细胞色素B的还原位点作为其细胞靶点。 与还原和氧化位点抑制剂的组合实验显示了对寄生虫的协同抑制。结论：细胞色素B氧化中心是一个有效的抗疟靶点。 我们发现细胞色素B的还原位点也是一个药物靶点。我们的研究结果表明，氧化和还原位点抑制剂之间的协同作用关系，提出了一个新的组合疗法在治疗疟疾的未来战略。
Background. The emergence and spread of drug resistance to current antimalarial therapies remains a pressing concern, escalating the need for compounds that demonstrate novel modes of action. Diversity-Oriented Synthesis (DOS) libraries bridge the gap between conventional small molecule and natural product libraries, allowing the interrogation of more diverse chemical space in efforts to identify probes of novel parasite pathways. Methods. We screened and optimized a probe from a DOS library using whole-cell phenotypic assays. Resistance selection and whole-genome sequencing approaches were employed to identify the cellular target of the compounds. Results. We identified a novel macrocyclic inhibitor of Plasmodium falciparum with nanomolar potency and identified the reduction site of cytochrome b as its cellular target. Combination experiments with reduction and oxidation site inhibitors showed synergistic inhibition of the parasite. Conclusions. The cytochrome b oxidation center is a validated antimalarial target. We show that the reduction site of cytochrome b is also a druggable target. Our results demonstrating a synergistic relationship between oxidation and reduction site inhibitors suggests a future strategy for new combination therapies in the treatment of malaria.
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影响因子：
4.2
作者：
Heidebrecht, Richard W., Jr.;Mulrooney, Carol;Austin, Christopher P.;Barker, Robert H., Jr.;Beaudoin, Jennifer A.;Cheng, Ken Chih-Chien;Comer, Eamon;Dandapani, Sivaraman;Dick, Justin;Duvall, Jeremy R.;Ekland, Eric H.;Fidock, David A.;Fitzgerald, Mark E.;Foley, Michael;Guha, Rajarshi;Hinkson, Paul;Kramer, Martin;Lukens, Amanda K.;Masi, Daniela;Marcaurelle, Lisa A.;Su, Xin-Zhuan;Thomas, Craig J.;Weiwer, Michel;Wiegand, Roger C.;Wirth, Dyann;Xia, Menghang;Yuan, Jing;Zhao, Jinghua;Palmer, Michelle;Munoz, Benito;Schreiber, Stuart
通讯作者：
Schreiber, Stuart
影响因子：
4
作者：
Nam, Tae-gyu;McNamara, Case W.;Winzeler, Elizabeth A.
通讯作者：
Winzeler, Elizabeth A.
影响因子：
17.1
作者：
Nilsen A;LaCrue AN;White KL;Forquer IP;Cross RM;Marfurt J;Mather MW;Delves MJ;Shackleford DM;Saenz FE;Morrisey JM;Steuten J;Mutka T;Li Y;Wirjanata G;Ryan E;Duffy S;Kelly JX;Sebayang BF;Zeeman AM;Noviyanti R;Sinden RE;Kocken CHM;Price RN;Avery VM;Angulo-Barturen I;Jiménez-Díaz MB;Ferrer S;Herreros E;Sanz LM;Gamo FJ;Bathurst I;Burrows JN;Siegl P;Guy RK;Winter RW;Vaidya AB;Charman SA;Kyle DE;Manetsch R;Riscoe MK
通讯作者：
Riscoe MK
影响因子：
4.9
作者：
Vallieres, Cindy;Fisher, Nicholas;Meunier, Brigitte
通讯作者：
Meunier, Brigitte
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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