Descripción del proyecto
Actuación selectiva sobre estructuras de ADN no clásicas de los tripanosomas
La tripanosomiasis africana es una enfermedad de transmisión vectorial causada por el parásito «Trypanosoma», que se transmite a través de las moscas tse-tsé, endémicas en el África subsahariana. Tras entrar en el aparato circulatorio y el sistema linfático, el parásito infecta el sistema nervioso central, lo cual puede resultar mortal. A pesar de que existe un tratamiento de primera línea eficaz, los temores por la farmacorresistencia han alentado a los científicos del proyecto financiado con fondos europeos SMART a investigar soluciones alternativas. Se proponen actuar sobre las estructuras secundarias de ADN denominadas G-cuádruples, que habitualmente forman el ADN telomérico de muchas especies. A través del desarrollo de moléculas diseñadas para actuar selectivamente sobre las estructuras G-cuádruples del tripanosoma, los investigadores estudiarán el papel de estas últimas en la biología del tripanosoma.
Objetivo
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.
Ámbito científico
Not validated
Not validated
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
SW7 2AZ LONDON
Reino Unido