Journal Article

PUBDB-2026-01398

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Repurposing of Inhibitors of Plasmodial Aspartate Transcarbamoylase Toward Trypanosoma Cruzi

Chen, S. ; Cal, M. ; Mondile, Q. ; Oerlemans, R. ; Shashikant, M. M. ; Dömling, A. S. S. ; Bishop, Ö. T. ; Mäser, P. ; Groves, M. (Corresponding author)Extern*

2026
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/cmdc.202500817  doi:10.3204/PUBDB-2026-01398

Abstract: Aspartate transcarbamoylase (ATC) catalyzes the committed and rate-limiting step in the pyrimidine de novo biosynthesis pathway. While previously suggested to be a potential target for antimalarial, antitubercular, and antioncologic drug discovery, we hypothesized that an existing compound library of ATC inhibitors designed from one scaffold by fragment screening against Plamodium falciparum ATC (PfATC) may also contain inhibitors of Trypanosoma cruzi ATC (TcATC). In this manuscript, we screened the 70-member library at 35 μM against 50 nM TcATC, and in these initial experiments, 34 compounds showed over 90% inhibition. Of the 34 compounds, 5 compounds demonstrated IC50 values of lower than 250 nM in a follow-up enzymatic half inhibition concentration analysis. Kinetic studies on one of these compounds indicate that they inhibit TcATC in a noncompetitive manner, and a druggable allosteric pocket is seen in the available crystal structure. While cocrystallization and soaking experiments were unsuccessful, molecular modeling was performed to assess potential binding modes. Two of the best-performing compounds were selected for a cellular assay, showing EC50s of 7.4 µM and 6.5 µM. However, significant cotoxicity was also observed, demonstrating that further elaboration of the compounds is necessary. These results suggest that this compound library might be a starting point for antitrypanosomatid drug discovery.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P11 (PETRA III)
2. PETRA Beamline P13 (PETRA III)

Appears in the scientific report 2026

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Database coverage:
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