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Published on: June 23, 2022
Fragment-Based Identification of Ligands for Bromodomain-Containing Factor 3 of Trypanosoma cruzi
Corentine M C Laurin1, Joseph P Bluck1,2, Anthony K N Chan1
1Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
Insights
Researchers identified small molecules that bind to a key protein in the Trypanosoma cruzi parasite, the cause of Chagas disease. These novel ligands offer new tools to study parasite biology and develop treatments.
Area of Science:
- Parasitology
- Epigenetics
- Drug Discovery
Background:
- Chagas disease, caused by the Trypanosoma cruzi parasite, is a significant health concern in South America.
- Trypanosoma cruzi exhibits complex life cycle stage transitions potentially regulated by epigenetic mechanisms.
- The function of Trypanosoma cruzi bromodomain-containing factors (TcBDFs) remains largely uncharacterized.
Purpose of the Study:
- To identify ligands targeting Trypanosoma cruzi bromodomain-containing factor 3 (TcBDF3).
- To develop novel chemical probes for studying TcBDF3 function and T. cruzi biology.
Main Methods:
- Expressed a soluble TcBDF3 protein construct in E. coli.
- Developed biophysical assays for protein characterization.
- Performed fragment screening to identify small molecule binders to the TcBDF3 bromodomain.
Main Results:
- Identified 12 compounds that bind to the TcBDF3 bromodomain.
- Developed functional ligands incorporating reporter groups (fluorescence or 19F).
- Created a photo-crosslinking probe for TcBDF3.
Conclusions:
- The identified ligands and probes serve as valuable tools for future research on TcBDF3.
- These tools will advance the understanding of Trypanosoma cruzi biology and epigenetic regulation.
- This work lays the foundation for potential therapeutic strategies against Chagas disease.
Abstract:
The Trypanosoma cruzi (T. cruzi) parasite is the cause of Chagas disease, a neglected disease endemic in South America. The life cycle of the T. cruzi parasite is complex and includes transitions between distinct life stages. This change in phenotype (without a change in genotype) could be controlled by epigenetic regulation, and might involve the bromodomain-containing factors 1-5 (TcBDF1-5). However, little is known about the function of the TcBDF1-5. Here we describe a fragment-based approach to identify ligands for T. cruzi bromodomain-containing factor 3 (TcBDF3). We expressed a soluble construct of TcBDF3 in E. coli, and used this to develop a range of biophysical assays for this protein. Fragment screening identified 12 compounds that bind to the TcBDF3 bromodomain. On the basis of this screen, we developed functional ligands containing a fluorescence or 19F reporter group, and a photo-crosslinking probe for TcBDF3. These tool compounds will be invaluable in future studies on the function of TcBDF3 and will provide insight into the biology of T. cruzi.
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