Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials.
Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials.
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DOI：
10.1021/cb500616x
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发表时间：
2015-02-20
影响因子：
4
通讯作者：
Winzeler, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Flannery, Erika L.;McNamara, Case W.;Kim, Sang Wan;Kato, Tomoyo Sakata;Li, Fengwu;Teng, Christine H.;Gagaring, Kerstin;Manary, Micah J.;Barboa, Rachel;Meister, Stephan;Kuhen, Kelli;Vinetz, Joseph M.;Chatterjee, Arnab K.;Winzeler, Elizabeth A.
氨基吡唑类化合物是一类新的抗疟化合物，在细胞抗寄生虫筛选中鉴定出对恶性疟原虫无性和有性阶段寄生虫具有有效活性。为了研究其未知的作用机制，从而确定其靶标，我们在氨基吡唑系列的代表性成员GNF-Pf 4492存在下培养寄生虫，以选择抗性。三个抗性品系的全基因组测序显示，每个抗性品系都在P型阳离子转运蛋白ATP酶PfATP 4（PF3D7_1211900）中获得了独立的突变，PfATP 4是一种与新型疟原虫属（Plasmodium spp.）另一类结构上不相关的抗疟药螺吲哚酮的靶点，是细胞重要的钠转运蛋白。与螺吲哚酮类似，GNF-Pf 4492阻断寄生虫向蚊子的传播并破坏细胞内钠稳态。我们的数据表明，PfATP 4在细胞过程中起着关键作用，可以被两种不同的抗疟药效团抑制，并支持最近的观察结果，PfATP 4是一个关键的抗疟目标。
Aminopyrazoles are a new class of antimalarial compounds identified in a cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism of action and thus identify their target, we cultured parasites in the presence of a representative member of the aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing of three resistant lines showed that each had acquired independent mutations in a P-type cation-transporter ATPase, PfATP4 (PF3D7_1211900), a protein implicated as the novel Plasmodium spp. target of another, structurally unrelated, class of antimalarials called the spiroindolones and characterized as an important sodium transporter of the cell. Similarly to the spiroindolones, GNF-Pf4492 blocks parasite transmission to mosquitoes and disrupts intracellular sodium homeostasis. Our data demonstrate that PfATP4 plays a critical role in cellular processes, can be inhibited by two distinct antimalarial pharmacophores, and supports the recent observations that PfATP4 is a critical antimalarial target.
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DOI：
10.1038/nrmicro3138
发表时间：
2013-12
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
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结构引导的三唑嘧啶环取代基的铅优化鉴定出具有临床候选潜力的有效的恶性疟原虫二氢二酸二氢二酸脱氢酶抑制剂。
影响因子：
7.3
作者：
Coteron, Jose M.;Marco, Maria;Esquivias, Jorge;Deng, Xiaoyi;White, Karen L.;White, John;Koltun, Maria;El Mazouni, Farah;Kokkonda, Sreekanth;Katneni, Kasiram;Bhamidipati, Ravi;Shackleford, David M.;Angulo-Barturen, Inigo;Ferrer, Santiago B.;Belen Jimenez-Diaz, Maria;Gamo, Francisco-Javier;Goldsmith, Elizabeth J.;Charman, William N.;Bathurst, Ian;Floyd, David;Matthews, David;Burrows, Jeremy N.;Rathod, Pradipsinh K.;Charman, Susan A.;Phillips, Margaret A.
通讯作者：
Phillips, Margaret A.
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：
5.6
作者：
Kortagere S;Welsh WJ;Morrisey JM;Daly T;Ejigiri I;Sinnis P;Vaidya AB;Bergman LW
通讯作者：
Bergman LW