Journal
MICROORGANISMS
Volume 10, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/microorganisms10071287
Keywords
MMV Pathogen Box; Human African Trypanosomiasis; Chagas disease; Trypanosoma cruzi; Trypanosoma brucei; image-based assays; high-content imaging; speed of action; time-kill assay; cidal activity; T; cruzi cytochrome P450; antitrypanosomal
Categories
Funding
- Griffith University Postdoctoral Fellowship (GUPF)
- Drugs for Neglected Diseases initiative (DNDi)
- DNDi
- Swiss Agency for Development and Cooperation (SDC), Switzerland
- Directorate General for International Cooperation (DGIS), The Netherlands
- (DFID), UK
- Medecins Sans Frontieres, international
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Chagas disease and Human African Trypanosomiasis (HAT) are parasitic diseases that pose a serious threat to human health. The existing treatment methods are not highly effective, thus there is a need for new therapeutic drugs. Through in vitro assays, compounds with selective activity against these parasites have been identified and evaluated for further research and development.
Chagas disease caused by the protozoan Trypanosoma cruzi is endemic to 21 countries in the Americas, effects approximately 6 million people and on average results in 12,000 deaths annually. Human African Trypanosomiasis (HAT) is caused by the Trypanosoma brucei sub-species, endemic to 36 countries within sub-Saharan Africa. Treatment regimens for these parasitic diseases are complicated and not effective against all disease stages; thus, there is a need to find improved treatments. To identify new molecules for the drug discovery pipelines for these diseases, we have utilised in vitro assays to identify compounds with selective activity against both T. cruzi and T.b. brucei from the Medicines for Malaria Venture (MMV) Pathogen Box compound collection. To prioritise these molecules for further investigation, temporal and wash off assays were utilised to identify the speed of action and cidality of compounds. For translational relevance, compounds were tested against clinically relevant T.b. brucei subspecies. Compounds with activity against T. cruzi cytochrome P450 (TcCYP51) have not previously been successful in clinical trials for chronic Chagas disease; thus, to deprioritise compounds with this activity, they were tested against recombinant TcCYP51. Compounds with biological profiles warranting progression offer important tools for drug and target development against kinetoplastids.
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