Drugs for Trypanosomal Diseases
Identifying novel drug targets for sleeping sickness, Chagas disease, and leishmaniasis
Dr. Ken Stuart has expertise in developing and screening drugs for human African trypanosomiasis (sleeping sickness), Chagas disease, and leishmaniasis. These diseases are caused by a group of related trypanosomal parasites, called kinetoplastids, and his group was instrumental in sequencing and interpreting the genomes of these three pathogens. The Stuart lab uses the genetically tractable Trypanosoma brucei as a model to study these parasites. They are now using various methods for drug discovery using this organism that employ gene editing and knockdown, and overexpression of target genes.
Dr. Stuart's lab has used a systems approach to identify multiple kinetoplastid pathways with potential drug targets. These include a mitochondrial RNA-editing process that they discovered and which is unique to and essential for the survival of the parasites. They are characterizing the components of the RNA-editing machinery to validate druggable targets. They also identified a tRNA synthetase with drug-development potential and developed an assay for the enzyme's activity and used it to screen potential drug leads.
While investigating the antigenic-variation process that T. brucei uses to change cell-surface glycoproteins and thus evade the immune system, the Stuart lab made another discovery. They found that antigenic variation and critical steps in T. brucei life cycle development are controlled by the inositol phosphate system genes. Almost every step in this system is essential to the parasite thus presenting multiple therapeutic targets. By screening a library of kinase inhibitors, the Stuart group found small compounds that inhibit the parasite's inositol polyphosphate multikinase (IPMK) enzyme, parasite growth, and the ability to infect mice. Early evidence with T. brucei models of Chagas and leishmaniasis supports inhibition of IPMK as a therapeutic strategy for these diseases.The inositol polyphosphate enzymes differ from human enzymes, and thus may have broad applicability as drug targets among parasitic diseases.
The Stuart group is interested in partnerships that use their expertise in high-throughput, target-based drug development and screening of small-molecule compounds against African trypanosomiasis, Chagas disease, and leishmaniasis. They have experience and facilities for using their T. brucei model in vivo and in mouse models of infection.
Stage of Development
- Preclinical in vitro
- Preclinical ex vivo
- Preclinical in vivo
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- High-throughput screening
- Cestari I, Haas P, Moretti NS, Schenkman S, Stuart K. Chemogenetic characterization of inositol phosphate metabolic pathway reveals druggable enzymes for targeting kinetoplastid parasites. Cell Chem Biol. 2016;23:608-617.
- Cestari I, Stuart K. Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes. Proc Natl Acad Sci USA. 2015;12(21):E2803-2812.
- Cestari I, Stuart K. Inhibition of isoleucyl-tRNA synthetase as a potential treatment for human African trypanosomiasis. J Biol Chem. 2013;288(20):14256-14263.
- Cestari I, Stuart K. A spectrophotometric assay for quantitative measurement of aminoacyl-tRNA synthetase activity. J Biomol Screen. 2013;18(4):490-497.