Research School of Biology, Australian National University, Canberra, ACT 2601, Australia.
Sci Rep. 2018 Jun 11;8(1):8795. doi: 10.1038/s41598-018-26819-1.
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.
四百种结构多样的类药性化合物，构成了疟疾药物倡议的“病原体盒”，对其在无性血阶段疟原虫（恶性疟原虫）寄生虫中的一系列生理参数的影响进行了筛选。其中 11 种化合物被发现以与抑制假定的 Na 外排 P 型 ATP 酶 PfATP4 一致的方式扰乱寄生虫的 Na+、pH 和体积。这 11 种化合物都属于病原体盒中包含的 125 种化合物的子集，因为它们被鉴定为抑制无性血阶段恶性疟原虫寄生虫生长的有效抑制剂。这 11 种化合物均抑制寄生虫膜的 Na 依赖性 ATP 酶活性，对携带 PfATP4 突变的寄生虫的疗效降低。这项研究增加了已知表现出“与 PfATP4 相关”表型的化学结构多样性的数量，并为越来越多的证据增添了证据，即在整个细胞表型筛选中确定的结构多样的抗疟化合物中，有很大比例（7-9%）具有相同的作用机制，通过与 PfATP4 的相互作用发挥其抗疟作用。
