Description du projet
Cibler les structures d’ADN non canonique dans les trypanosomes
La maladie du sommeil ou trypanosomiase africaine est une maladie à transmission vectorielle causée par le parasite Trypanosoma, qui est transmis par la mouche tsé-tsé, endémique de l’Afrique subsaharienne. Une fois dans les systèmes sanguin et lymphatique, le parasite infecte le système nerveux central, ce qui peut s’avérer fatal. Bien qu’il existe un traitement de première intention efficace, les craintes d’une résistance aux médicaments ont poussé les scientifiques du projet SMART, financé par l’UE, à envisager d’autres solutions. Le projet propose de cibler des structures secondaires de l’ADN appelées G-quadruplexes, qui se forment normalement dans l’ADN télomérique de nombreuses espèces. En développant des molécules conçues pour cibler de manière sélective les G-quadruplexes du trypanosome, les chercheurs étudieront le rôle de ces derniers dans la biologie du trypanosome.
Objectif
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.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
SW7 2AZ LONDON
Royaume-Uni