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Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Aug 07; Vol. 68 (8), pp. e0024324. Date of Electronic Publication: 2024 Jul 19. - Publication Year :
- 2024
-
Abstract
- Bromodomains are structural folds present in all eukaryotic cells that bind to other proteins recognizing acetylated lysines. Most proteins with bromodomains are part of nuclear complexes that interact with acetylated histone residues and regulate DNA replication, transcription, and repair through chromatin structure remodeling. Bromodomain inhibitors are small molecules that bind to the hydrophobic pocket of bromodomains, interfering with the interaction with acetylated histones. Using a fluorescent probe, we have developed an assay to select inhibitors of the bromodomain factor 2 of Trypanosoma cruzi ( Tc BDF2) using fluorescence polarization. Initially, a library of 28,251 compounds was screened in an endpoint assay. The top 350-ranked compounds were further analyzed in a dose-response assay. From this analysis, seven compounds were obtained that had not been previously characterized as bromodomain inhibitors. Although these compounds did not exhibit significant trypanocidal activity, all showed bona fide interaction with Tc BDF2 with dissociation constants between 1 and 3 µM validating these assays to search for bromodomain inhibitors.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Transcription Factors antagonists & inhibitors
Transcription Factors metabolism
Trypanosoma cruzi drug effects
Trypanosoma cruzi metabolism
Fluorescence Polarization
Protozoan Proteins antagonists & inhibitors
Protozoan Proteins metabolism
Trypanocidal Agents pharmacology
Trypanocidal Agents chemistry
High-Throughput Screening Assays methods
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 68
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 39028190
- Full Text :
- https://doi.org/10.1128/aac.00243-24