Synthesis, photoswitching, and RNA-binding properties of aurone derivatives and conjugates of 2-deoxystreptamine with hemi-indigo-type photochromes

• Applicant: Dr. Daria Berdnikova
• Subject Area: Biological and Biomimetic Chemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437120393

The development of the RNA-targeting therapy is tightly connected with the development of small organic molecules capable of efficient and selective interactions with disease-related RNA sequences. Nevertheless, up to now only four fully synthetic small molecules are applied as RNA-targeting drugs in clinical practice, which reflects the significant challenges accompanying the design of RNA binders and the urgency to identify new lead structures. The proposed project addresses the development of functional RNA ligands in two approaches. In the first sub-project, photoswitchable dimers of 2-deoxystreptamine, which is the essential building block of aminoglycoside antibiotics, will be synthesized and their interactions with therapeutically relevant RNA sequences will be studied. The special focus will be on the selection of naturally occurring RNA targets, which provide unique binding pockets for ligands. The main goal of this sub-project is to realize the light-controllable change of the ligand–RNA binding mode and photoswitchable RNA unfolding, which shall represent a molecular basis for the potential therapeutical effect. In the second sub-project, aurones and isoaurones will be synthesized. Based on our recent findings on the remarkable photoswitching of aurones in water as well as their bright fluorescence in both solution and solid state, it is proposed to develop these compounds as photoswitchable RNA binders and fluorescent probes for RNA diagnostics. Therefore, fluorescent properties of aurones and isoaurones in solution and in the solid state will be investigated and their photoswitching and RNA staining will be studied to establish and apply this class of compounds for targeting and detection of disease-related RNAs. In a new methodical approach, the photochemical reactions will be analyzed in real time by a home-made LED-equipped NMR spectrometer that enables the direct irradiation of the sample inside the spectrometer. Subsequently, in the context of biological studies, the most promising RNA-binding ligands will be tested as light-controllable antibiotics against selected bacterial strains and as photoswitchable binders and markers for disease-related RNA sequences, e.g. RNA CAG expansions. In this part, in-cell NMR-spectroscopic experiments are also planned as an innovative feature of this project that allows the investigation of the structure and interactions of biomolecules in the complex environment of living cells. Overall, it is anticipated that this project will (i) contribute to the understanding of the design and selectivity principles of photoswitchable aminoglycoside antibiotics, (ii) provide the basis for the application of aurones and isoaurones as functional RNA binders and fluorescent probes, (iii) identify and develop novel lead structures for RNA-targeting therapy.

• DFG Programme: Research Grants