Descrizione del progetto
Targeting delle strutture non canoniche del DNA nei tripanosomi
La malattia del sonno o tripanosomiasi africana è una malattia trasmessa da vettori causata dal parassita Trypanosoma, che viene trasmesso dalla mosca tse-tse, endemica nell’Africa subsahariana. Dopo essere entrato nel sangue e nei sistemi linfatici, il parassita infetta il sistema nervoso centrale, con esiti anche fatali. Sebbene esista un approccio terapeutico efficace di prima linea, i timori per la farmacoresistenza hanno spinto gli scienziati del progetto SMART, finanziato dall’UE, a studiare soluzioni alternative. Il progetto propone di bersagliare strutture secondarie del DNA note come G-quadruplex, che normalmente si formano nel DNA telomerico di molte specie. Attraverso lo sviluppo di molecole progettate per colpire selettivamente i G-quadruplex del tripanosoma, i ricercatori studieranno il ruolo di questi ultimi nella biologia del tripanosoma.
Obiettivo
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.
Campo scientifico
Not validated
Not validated
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
SW7 2AZ LONDON
Regno Unito