Hypothesis-generating proteome perturbation to identify NEU-4438 and acoziborole modes of action in the African Trypanosome.
Hypothesis-generating proteome perturbation to identify NEU-4438 and acoziborole modes of action in the African Trypanosome.
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DOI：
10.1016/j.isci.2022.105302
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发表时间：
2022-11-18
期刊：
影响因子：
5.8
通讯作者：
Mensa-Wilmot, Kojo
中科院分区：
文献类型：
--
作者：
Sharma, Amrita;Cipriano, Michael;Ferrins, Lori;Hajduk, Stephen L.;Mensa-Wilmot, Kojo
NEU-4438是开发抗布氏锥虫药物的领导者，布氏锥虫导致人类非洲锥虫病。通过表型筛选优化，NEU-4438的靶点未知。在本文中，我们提出了一种细胞扰动组工作流程，将NEU-4438的分子作用模式与SCYX-7158（acoziborole）的分子作用模式进行了比较。锥虫6小时扰动后，NEU-4438和acoziborole分别减少了68和92个独特蛋白质的稳态量。蛋白质组分析后，对作用模式的假设进行了测试：Acoziborole和NEU-4438具有不同的作用模式。而NEU-4438阻止DNA生物合成和基体成熟，acoziborole使CPSF 3和其他蛋白质不稳定，抑制多肽翻译，并减少结合珠蛋白-血红蛋白的内吞作用。这些数据表明acoziborole的CPSF 3独立作用模式。在多种药理学的情况下，细胞扰动工作流程阐明了作用模式，因为它是靶不可知的。最后，该工作流程可用于任何适合蛋白质组学和分子生物学实验的细胞。细胞扰动组蛋白质组学鉴定药物添加后不稳定的多肽药物诱导的细胞蛋白质组变化用于开发MOA的假设实验测试验证了为NEU-4438和acoziborole制定的假设基于细胞扰动的MOA预测工作流程适用于所有细胞类型微生物学;寄生虫学;组学;蛋白质组学
NEU-4438 is a lead for the development of drugs against Trypanosoma brucei, which causes human African trypanosomiasis. Optimized with phenotypic screening, targets of NEU-4438 are unknown. Herein, we present a cell perturbome workflow that compares NEU-4438’s molecular modes of action to those of SCYX-7158 (acoziborole). Following a 6 h perturbation of trypanosomes, NEU-4438 and acoziborole reduced steady-state amounts of 68 and 92 unique proteins, respectively. After analysis of proteomes, hypotheses formulated for modes of action were tested: Acoziborole and NEU-4438 have different modes of action. Whereas NEU-4438 prevented DNA biosynthesis and basal body maturation, acoziborole destabilized CPSF3 and other proteins, inhibited polypeptide translation, and reduced endocytosis of haptoglobin-hemoglobin. These data point to CPSF3-independent modes of action for acoziborole. In case of polypharmacology, the cell-perturbome workflow elucidates modes of action because it is target-agnostic. Finally, the workflow can be used in any cell that is amenable to proteomic and molecular biology experiments. Cell perturbome proteomics identified polypeptides destabilized after drug addition Changes in cellular proteomes induced by drugs were used to develop hypotheses for MOA Experimental tests verified hypotheses formulated for NEU-4438 and acoziborole Cell perturbomics-based workflow for the prediction of MOA is applicable to all cell types Microbiology; Parasitology; Omics; Proteomics
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影响因子：
11.2
作者：
Dai CL;Tiwari AK;Wu CP;Su XD;Wang SR;Liu DG;Ashby CR Jr;Huang Y;Robey RW;Liang YJ;Chen LM;Shi CJ;Ambudkar SV;Chen ZS;Fu LW
通讯作者：
Fu LW
影响因子：
5.3
作者：
Hartmann S;Nusbaum DJ;Kim K;Alameh S;Ho CC;Cruz RL;Levitin A;Bradley KA;Martchenko M
通讯作者：
Martchenko M
影响因子：
4.6
作者：
Benz C;Dondelinger F;McKean PG;Urbaniak MD
通讯作者：
Urbaniak MD
影响因子：
1.5
作者：
Burkard, Gabriela;Fragoso, Cristina M.;Roditi, Isabel
通讯作者：
Roditi, Isabel
影响因子：
2.8
作者：
de Oliveira Silva Nunes, Debora Cristina;Costa, Monica Soares;Bispo-da-Silva, Luiz Borges;Vieira Ferro, Eloisa Amalia;Pereira Zoia, Mariana Alves;Goulart, Luiz Ricardo;Rodrigues, Renata Santos;Rodrigues, Veridiana de Melo;Geraldo Yoneyama, Kelly Aparecida
通讯作者：
Geraldo Yoneyama, Kelly Aparecida