Back to search

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Paving the way for rational RNA-ligand design

Alternative title: Baner vei for rasjonell RNA-liganddesign

Awarded: NOK 9.6 mill.

The vast majority of targets for approved drugs are proteins. In recent years, it has been increasingly realized that also RNA molecules constitute promising targets. However, compared to protein targets, they are vastly underexplored. By targeting RNA, the functions of currently undruggable protein-mediated pathways and the non-coding transcriptome can be modulated and thus the size of the druggable genome can be increased substantially. A major obstacle in RNA-targeting drug discovery is the lack of knowledge on how to obtain drug-like RNA ligands. The main goal of this project is therefore to establish a blueprint on how to design drug-like, potent, selective, and functional RNA ligands based on the 3D structure of the target and to advance our understanding of what drives potency and selectivity of RNA ligands on the molecular level. Focusing on RNA targets that contain druggable binding site will allow us to transfer methods that are at the forefront in structure-based design in the protein field to RNA. We have chosen two emerging targets for antibiotics, the FMN and TPP riboswitches (genetic switches in bacterial mRNA), as model systems. Hit compounds will be advanced through “design-synthesis-test” cycles and extensively characterized in terms of binding affinity and kinetics, functional activity, selectivity, and binding modes. This will deliver detailed knowledge about RNA-ligand interactions which is crucial to advance RNA-targeted drug discovery. In addition, the project will deliver advanced starting points for antibiotic drug discovery. We anticipate that this study will lead to a paradigm shift in the RNA field away from the currently rather unsuccessful “one size fits all” approach to a more target-centred approach where the nature of the binding site is taken into account. To achieve the ambitious goals, we have assembled an interdisciplinary team of experts in RNA biology, structure-based design, medicinal and organic chemistry, and drug discovery.

The vast majority of targets for approved drugs are proteins. In recent years, it has been increasingly realized that also RNA molecules constitute promising targets. However, compared to protein targets, they are vastly underexplored. By targeting RNA, the functions of currently undruggable protein-mediated pathways and the non-coding transcriptome can be modulated and thus the size of the druggable genome can be increased substantially. A major obstacle in RNA-targeting drug discovery is the lack of knowledge on how to obtain drug-like RNA ligands. The main goal of this project is therefore to establish a blueprint on how to design drug-like, potent, selective, and functional RNA ligands based on the 3D structure of the target and to advance our understanding of what drives potency and selectivity of RNA ligands on the molecular level. Focusing on RNA targets that contain druggable binding site will allow us to transfer methods that are at the forefront in structure-based design in the protein field to RNA. We have chosen two emerging targets for antibiotics, the FMN and TPP riboswitches (genetic switches in bacterial mRNA), as model systems. Hit compounds will be advanced through “design-synthesis-test” cycles and extensively characterized in terms of binding affinity and kinetics, functional activity, selectivity, and binding modes. This will deliver detailed knowledge about RNA-ligand interactions which is crucial to advance RNA-targeted drug discovery. In addition, the project will deliver advanced starting points for antibiotic drug discovery. We anticipate that this study will lead to a paradigm shift in the RNA field away from the currently rather unsuccessful “one size fits all” approach to a more target-centred approach where the nature of the binding site is taken into account. To achieve the ambitious goals, we have assembled an interdisciplinary team of experts in RNA biology, structure-based design, medicinal and organic chemistry, and drug discovery.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Funding Sources