Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites.
Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites.
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DOI：
10.1038/s41598-021-81486-z
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发表时间：
2021-01-22
影响因子：
4.6
通讯作者：
Fidock DA
中科院分区：
文献类型：
--
作者：
Dorjsuren D;Eastman RT;Wicht KJ;Jansen D;Talley DC;Sigmon BA;Zakharov AV;Roncal N;Girvin AT;Antonova-Koch Y;Will PM;Shah P;Sun H;Klumpp-Thomas C;Mok S;Yeo T;Meister S;Marugan JJ;Ross LS;Xu X;Maloney DJ;Jadhav A;Mott BT;Sciotti RJ;Winzeler EA;Waters NC;Campbell RF;Huang W;Simeonov A;Fidock DA
恶性疟原虫寄生虫对大多数一线抗疟药物具有耐药性，这种寄生虫的传播迫切需要丰富药物发现渠道，最好是使用也可以发挥抗疟作用的治疗性化合物。我们报告了一个表型定量高通量筛选（qHTS），基于浓度-反应曲线，其目的是确定化合物对疟原虫肝脏和无性血液阶段寄生虫的活性。我们的qHTS筛选了超过450，000种化合物，在5至11种浓度范围内进行了测试，以确定其对恶性疟原虫无性血液阶段的活性。然后过滤活性化合物的独特结构和药物样性质，随后在伯氏疟原虫肝脏阶段测定中筛选以鉴定新的双重活性抗疟原虫化学型。随后将来自噻二嗪和嘧啶氮杂卓化学型的命中物优先用于抗性选择研究，从而在恶性疟原虫细胞色素B（一种经验证的抗疟药物靶标）中产生不同的突变。噻二嗪化学型进行了初步的药物化学活动，产生了亚微摩尔效力的代谢稳定的类似物。我们的qHTS方法和所得数据集提供了一个大规模的资源，以调查疟原虫肝脏和无性血液阶段寄生虫生物学，并为进一步的研究提供信息，以开发新的化学型作为因果预防性抗疟药。
The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration–response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials.
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影响因子：
1.5
作者：
Ganesan, Suresh M.;Morrisey, Joanne M.;Ke, Hangjun;Painter, Heather J.;Laroiya, Kamal;Phillips, Margaret A.;Rathod, Pradipsinh K.;Mather, Michael W.;Vaidya, Akhil B.
通讯作者：
Vaidya, Akhil B.
影响因子：
5.7
作者：
Chu CS;White NJ
通讯作者：
White NJ
DOI：
10.1073/pnas.91.3.1143
发表时间：
1994-02-01
影响因子：
11.1
作者：
COWMAN, AF;GALATIS, D;THOMPSON, JK
通讯作者：
THOMPSON, JK
影响因子：
168.9
作者：
Cissé, B;Sokhna, C;Trape, JF
通讯作者：
Trape, JF
影响因子：
4.9
作者：
Guler, Jennifer L.;White, John, III;Rathod, Pradipsinh K.
通讯作者：
Rathod, Pradipsinh K.