Hypothesis-generating proteome perturbation to identify NEU-4438 and acoziborole modes of action in the African Trypanosome

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 S...

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Bibliographic Details
Published iniScience Vol. 25; no. 11; p. 105302
Main Authors Sharma, Amrita, Cipriano, Michael, Ferrins, Lori, Hajduk, Stephen L., Mensa-Wilmot, Kojo
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 18.11.2022
Elsevier
Subjects
Microbiology
omics
parasitology
proteomics
Microbiology
omics
proteomics
parasitology
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Summary: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. [Display omitted] •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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ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2022.105302