2014 PEW Latin American Fellowship for Armando Hernandez-Garcia

The development of therapeutic RNAs has created new opportunities to address “non-druggable” targets to cure a broad range of diseases, including cancer. Unfortunately, problems in the efficient and safe delivery of the therapeutic RNAs to their target sites are so far preventing their widespread use as a drug. We propose a new bio-inspired strategy for allosteric control of assembly/disassembly of protein-based nanoscale RNA delivery vehicles that can resolve the apparently conflicting demands of strong protection of vulnerable RNAs and efficient release once such vehicles reach their target sites, such as in cancer cells. The most difficult problem is switchable disassembly, and for this we propose to rely on the well known and reliable mechanism of the reduction of disulfide bridges inside living cells. By splitting an RNA binding domain in two halves, and linking each of these halves with self-assembling peptides that interact through disulfide bridges, we create allosteric control of RNA binding activity that is switchable via a redox potential. The strategy of split protein systems with an activity that is switchable via engineered self-assembling peptides is a novel and robust mechanism for responsive nanostructure delivery that could be applied to a wide range of therapeutic cargos. Hence, the work we propose paves the way for a new strategy to address and cure a wide range of public health problems.