Project description
Targeting non-canonical DNA structures in trypanosomes
Sleeping sickness or African trypanosomiasis is a vector-borne disease caused by the parasite Trypanosoma, which is transmitted by the tsetse fly, endemic in Sub-Saharan Africa. After entering the blood and lymph systems, the parasite infects the central nervous system, which may be fatal. Although there is an effective first-line treatment, fears for drug resistance have urged scientists of the EU-funded SMART project to investigate alternative solutions. The project proposes to target DNA secondary structures known as G-quadruplexes, which normally form in the telomeric DNA of many species. Through the development of molecules designed to selectively target trypanosome G-quadruplexes, researchers will study the role of the latter in trypanosome biology.
Objective
African trypanosomiasis (AT), caused by the protozoan parasite Trypanosoma spp., is a debilitating disease that threatens millions of people in Sub-Saharan Africa. The human disease evolves in two stages, the second of which causes a fatal neurological infection if left untreated. The recent discovery of the orally-bioavailable drug fexinidazole, and its current use as a first-line treatment, has significantly improved disease outcomes associated with AT. However, the risk of resistance to fexinidazole treatment is a major concern that highlights the need for new treatment options. G-quadruplexes (G4s) are non-canonical DNA secondary structures that have recently emerged as an attractive target to fight AT. For example, recent studies have revealed the killing properties of a well-characterised G4-ligand, quarfloxin, against T. brucei parasites, showing the great potential for G4-targeting approaches to treat AT. However, the fundamental role of G4s in trypanosome biology and their validation as therapeutic targets have not been elucidated. In this proposal, I aim to unravel the biological functions of G4s in trypanosomes using integrated chemistry and genomic approaches. Specifically, peptide-based molecules designed to selectively target trypanosome G4s (TG4) will be developed and biophysically validated. The TG4-selective peptides will be used to functionally interrogate the trypanosome genome and to understand the effect of G4-modulation on gene expression using transcriptomics. Finally, our peptides will be engineered into fluorescent probes to facilitate real-time molecular visualisations of TG4s formation in vitro, and to provide an in-depth characterisation of these structures as novel targets to combat AT.
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Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
SW7 2AZ LONDON
United Kingdom