The human pathogenic parasites Trypanosoma brucei and Trypanosoma cruzi exhibit unique metabolic features and pose a huge global burden on health and economic development. Powerful forward and reverse genetics methods, and whole-genome sequence information, facilitate studies of the basic parasite biology and potential drug targets. We study the “editosome”, a remarkable molecular machine in trypanosomal RNA biology, and participate in a multi-lab effort toward drug development against pathogenic trypanosomes. Our studies examine parasite life-cycle forms that infect the bloodstream and the insect vector of transmission.
RNA biology in trypanosomes
The editosome is a large molecular machine that remodels the mitochondrial transcriptome through extensive uridylate-specific indels. This process creates functional protein-coding sequences in primary mRNAs packed with stop codons. Trypanosomes diverged from other eukaryotic lineages over 100 Ma, yet RNA editing, RNA interference, CRISPR, and mRNA splicing exhibit interesting analogies such as the use of non-coding guide RNAs. Our long-term goal is to dissect the editosome regulatory mechanisms during the life stages of T. brucei. We currently study the organization and dynamic interaction of components in the editing apparatus, including an RNA helicase motor. These studies include an array of approaches including protein and RNA structure, bioinformatics, and proteomics.
J. Cruz-Reyes, B. H. M. Mooers, P. K. Doharey J. Meehan, S. Gulati, Dynamic RNA holo-editosomes with subcomplex variants: Insights into the control of trypanosome editing. WIREs RNA 9 (2018).
Development of lead compounds against trypanosomes
T. brucei and T. cruzi are the causative agents of critical human diseases, including African Sleeping Sickness and American Chagas Disease, respectively. We have an exciting collaboration with Tom Meek’s lab that proposes to develop lead drugs with selective inhibitory activity against essential proteins (targets) in pathogenic trypanosomes. We are testing drugs developed in the Meek lab against essential N-ribosyl transferases and cysteine proteases, including cruzain, rhodesain, and TbCatB. We use CRISPR gene editing among other tools to manipulate the expression of protein targets, validate their essentiality in transgenic parasites, and establish on-target specificity by candidate inhibitors.
B. C. Chenna, L. Li, D. M. Mellott, X. Zhai, J. L. Siqueira-Neto, C. C. Alvarez, J. A. Bernatchez, E. Desormeaux, E. Alvarez Hernandez, J. Gomez, J. H. McKerrow, J. Cruz-Reyes, T. D. Meek, Peptidomimetic vinyl heterocyclic Inhibitors of cruzain effect antitrypanosomal activity. J. Med. Chem. 63, 3298–3316 (2020).
To Academic Professional Track Faculty