Description du sujet de thèse

RNA targeting for the treatment of Fragile-X syndrome: target validation toward future drug discovery
Neurodevelopmental disorders represent a major public health burden since these diseases result in lifelong cognitive and behavioral deficits. Among them, fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and the leading monogenetic cause of Autism Spectrum Disorders (ASD). FXS is caused by the absence of expression of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, which ultimately leads to the lack of the encoded Fragile X Messenger RibonucleoProtein (FMRP). This latter usually binds to G-quadruplex structures in mRNA and regulates translation of protein targets. Given the absence of any treatment for FXS and the lack of relevant targets, we propose to validate G-quadruplexes in mRNAs as original and promising targets for synthetic RNA binders. To this aim, we will start from previously identified hits, confirm their molecular mechanism of action inside cells using target engagement experiments and increase their biological activity through medicinal chemistry optimization. The most active compounds will then be studied in vitro and in vivo using cellular and animal models mimicking FXS disorder. The main expected result from the development of this project is the validation of RNA G4 targeting approach as a potential treatment for FXS. The most active compounds could represent the first leads that would be further developed toward new drugs against this incurable disease.

Contexte de travail

Institut de Chimie de Nice (ICN), Faculté des Sciences,
28 avenue Valrose, 06100 Nice, France