SMART · Selective Molecular Approaches to Remove Trypanosomiasis
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-10-04 → 2023-10-03
- EU contribution
- €212,934
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Selective Molecular Approaches to Remove Trypanosomiasis
Human African trypanosomiasis (HAT) is a debilitating and deadly disease caused by the protozoan parasite Trypanosoma brucei spp. The disease threatens millions of people in Sub-Saharan Africa and represents a serious environmental, social, and economic burden for populations living in endemic areas. The recent discovery of the oral treatment fexinidazole has significantly improved disease outcomes, however, the risk of drug resistance remains a threat that requires the development of new treatment options. This project aims to characterise DNA structures, called G-quadruplexes (G4s), as novel cellular targets to treat and eradicate HAT. G4s are guanine-rich DNA sequences that self-assemble through G-G base pairing, forming a non-canonical DNA structure that can be found throughout the genome of all eukaryotes. For example, the human G4s have been widely characterised and validated as therapeutic targets, with novel G4-ligands entering clinical studies for cancer therapy. In contrast, parasitic G4s are still poorly characterised, and their potential as therapeutic targets is yet to be validated. In this proposal, we aim to characterise G4s in Trypanosoma brucei cells, using genomic approaches to determine the potential of these DNA structures as novel targets to fight parasitic infections.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union