Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Sharma A

PROVIDER: S-EPMC9593816 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Sharma Amrita A Cipriano Michael M Ferrins Lori L Hajduk Stephen L SL Mensa-Wilmot Kojo K

iScience 20221007 11

NEU-4438 is a lead for the development of drugs against <i>Trypanosoma brucei</i>, 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 proteom ...[more]

PMID: 36304107

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Project description:Historically, several different approaches have been applied to explain the metabolic cost of uphill human running. Most of these approaches result in unrealistically high values for the efficiency of performing vertical work during running uphill, or are only valid for running up steep inclines. The purpose of this study was to reexamine the metabolic cost of uphill running, based upon our understanding of level running energetics and ground reaction forces during uphill running. In contrast to the vertical efficiency approach, we propose that during incline running at a certain velocity, the forces (and hence metabolic energy) required for braking and propelling the body mass parallel to the running surface are less than during level running. Based on this idea, we propose that the metabolic rate during uphill running can be predicted by a model, which posits that (1) the metabolic cost of perpendicular bouncing remains the same as during level running, (2) the metabolic cost of running parallel to the running surface decreases with incline, (3) the delta efficiency of producing mechanical power to lift the COM vertically is constant, independent of incline and running velocity, and (4) the costs of leg and arm swing do not change with incline. To test this approach, we collected ground reaction force (GRF) data for eight runners who ran thirty 30-second trials (velocity: 2.0-3.0 m/s; incline: 0-9°). We also measured the metabolic rates of eight different runners for 17, 7-minute trials (velocity: 2.0-3.0 m/s; incline: 0-8°). During uphill running, parallel braking GRF approached zero for the 9° incline trials. Thus, we modeled the metabolic cost of parallel running as exponentially decreasing with incline. With that assumption, best-fit parameters for the metabolic rate data indicate that the efficiency of producing mechanical power to lift the center of mass vertically was independent of incline and running velocity, with a value of ∼29%. The metabolic cost of uphill running is not simply equal to the sum of the cost of level running and the cost of performing work to lift the body mass against gravity. Rather, it reflects a constant cost of perpendicular bouncing, decreased costs of parallel braking and propulsion and of course the cost of lifting body mass against gravity.

Dataset Information

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

Publications

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

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