Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis.
Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis.
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DOI：
10.1038/s41598-018-26819-1
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发表时间：
2018-06-11
影响因子：
4.6
通讯作者：
Kirk K
中科院分区：
文献类型：
--
作者：
Dennis ASM;Rosling JEO;Lehane AM;Kirk K
400种结构不同的药物样化合物组成的疟疾风险投资公司的“病原体盒”的药物进行了筛选，其对一系列生理参数的影响无性血液阶段疟疾（恶性疟原虫）寄生虫。发现这些化合物中的11种以与抑制推定的Na+流出P型ATP酶PfATP 4一致的方式扰乱寄生虫Na+、pH和体积。所有11种化合物都属于病原体盒中包括的125种化合物的子集，这是基于它们已被鉴定为无性血液阶段恶性疟原虫寄生虫生长的有效抑制剂。所有11种化合物抑制寄生虫膜的Na+依赖性ATP酶活性，并显示对携带PfATP 4突变的寄生虫的效力降低。这项研究增加了已知显示“PfATP 4相关”表型的化学多样性结构的数量，并增加了新出现的证据，即在全细胞表型筛选中鉴定的高比例（7-9%）的结构多样性抗疟化合物具有相同的作用机制，通过与PfATP 4的相互作用发挥其抗疟作用。
Four hundred structurally diverse drug-like compounds comprising the Medicines for Malaria Venture’s ‘Pathogen Box’ were screened for their effect on a range of physiological parameters in asexual blood-stage malaria (Plasmodium falciparum) parasites. Eleven of these compounds were found to perturb parasite Na+, pH and volume in a manner consistent with inhibition of the putative Na+ efflux P-type ATPase PfATP4. All eleven compounds fell within the subset of 125 compounds included in the Pathogen Box on the basis of their having been identified as potent inhibitors of the growth of asexual blood-stage P. falciparum parasites. All eleven compounds inhibited the Na+-dependent ATPase activity of parasite membranes and showed reduced efficacy against parasites carrying mutations in PfATP4. This study increases the number of chemically diverse structures known to show a ‘PfATP4-associated’ phenotype, and adds to emerging evidence that a high proportion (7–9%) of the structurally diverse antimalarial compounds identified in whole cell phenotypic screens share the same mechanism of action, exerting their antimalarial effect via an interaction with PfATP4.
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DOI：
10.1126/science.1193225
发表时间：
2010-09-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Rottmann M;McNamara C;Yeung BK;Lee MC;Zou B;Russell B;Seitz P;Plouffe DM;Dharia NV;Tan J;Cohen SB;Spencer KR;González-Páez GE;Lakshminarayana SB;Goh A;Suwanarusk R;Jegla T;Schmitt EK;Beck HP;Brun R;Nosten F;Renia L;Dartois V;Keller TH;Fidock DA;Winzeler EA;Diagana TT
通讯作者：
Diagana TT
影响因子：
4
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.
通讯作者：
Winzeler, Elizabeth A.
影响因子：
6.7
作者：
Hapuarachchi SV;Cobbold SA;Shafik SH;Dennis AS;McConville MJ;Martin RE;Kirk K;Lehane AM
通讯作者：
Lehane AM
DOI：
10.1073/pnas.1414221111
发表时间：
2014-12-16
影响因子：
11.1
作者：
Belen Jimenez-Diaz, Maria;Ebert, Daniel;Guy, R. Kiplin
通讯作者：
Guy, R. Kiplin
影响因子：
1.5
作者：
Allen, Richard J. W.;Kirk, Kiaran
通讯作者：
Kirk, Kiaran