Major bottlenecks in drug development are the identification of disease-relevant cellular targets and the subsequent development of safe and selective modulators of these targets. Since the vast majority of approved drugs addresses protein targets, it is curial to expand the space of targetable biomolecules, e.g. to Ribonucleic acids (RNA). RNA is highly under-represented drug targets and moved into the focus of drug discovery efforts, in particular, certain messenger RNAs (mRNA). RNA interference (RNAi) is an essential, post- transcriptional mechanism capable of degrading or blocking particular RNA sequences using short interfering RNA (siRNA) as starting point. Offering a specific and efficient means to suppress virtually any target gene, RNAi has become an indispensable research tool and has attracted significant interest as a therapeutic strategy. Despite considerable efforts, the widespread application of siRNA-based therapies has been limited due to a lack of effective intracellular delivery methods. Moreover, siRNA is degraded by ribonucleases which are omnipresent in cellular systems. These undesirable characteristics have fuelled efforts to develop delivery systems which disguise siRNA and facilitate its translocation and presentation to the RNAi machinery. However, so far a general solution that enables in vivo applications is lacking.
We have developed synthetic peptide-based molecules which facilitate structure-specific RNA binding and served as starting point for the design and synthesis of siRNA carriers. These carriers are composed of two RNA binding peptides that only bind their double-stranded RNA target in a homo-dimeric form. This is important as RNA cargo needs to be released once shuttled into the target cells. In our system, this is facilitated by a redox-sensitive disulfide bond between the two monomers which is cleaved upon reaching the reducing intracellular environment. We demonstrate that the stability and cellular permeability of RNA can be remarkably enhanced through complexation with the carrier molecules. The project aims to further demonstrate performance in a relevant environment thereby identifying a lead candidate. In addition, we aim to evaluate different exploitation strategies.
