Bioorthogonal Stapling of RNA

Significant advances in RNA research have brought this biomolecule in the spotlight of numerous scientific disciplines, therefore providing new opportunities for unraveling the biology of RNAs. Due to its key functions, enormous regulatory potential and association with various disorders, RNA has become an important target for diagnostics and drug design. Several molecular tools have been developed to target, manipulate and measure RNA and modulate its function. However, application of these strategies is still limited due to several reasons. The applicants of bioSTAR aim for the design and development of programmable chemical probes capable of selectively binding to a specific RNA sequence followed by a bioorthogonal ligation a chemical reaction that can proceed in living systems - locking the probe on its target. This approach will improve the binding to target RNA and furthermore enable the regulation of gene expression, which for example can be used to design new antibiotics based on the genetic code of bacteria. Hence, such probes can rapidly be redesigned if bacterial resistance arises due to mutation of the target, and thus may enable the development of last resort therapies against antibiotic-multiresistant bacteria. Furthermore, the bioorthogonal ligation can be designed in such a way that an active molecule is cleaved off (released) right upon and induced by the locking. We aim to use this cleavage mechanism to selectively release fluorescent reporters or highly potent drugs inside target cells. This will enable intracellular detection of RNA and sequence-specific delivery of drugs inside cancer cells enabling new strategies for precision medicine.