Abstract

The interaction of RNA-based therapeutics with proteins is an important contribution to their pharmacological properties. Clarifying and quantifying these binding mechanisms is unanimously considered as an essential factor that could help rationalize the design of any drug formulation containing RNA. The interaction with serum proteins is a crucial binding event that determines RNA-therapeutics circulation properties, including the one of ligand/nanoparticles used for their delivery. Despite its significance on the overall efficacy of the therapeutic, a lack of methodologies has lagged its understanding. In recent years several academic groups and pharmaceutical companies have taken over the challenge and proposed inventive analytical methods, Sixfold as one of them. Mergo, Sixfold’s proprietary delivery system, is a structured and chemically modified RNA, which is designed for cell-specific distribution of RNA-therapeutics. Mergos have shown different plasma protein binding properties and the team is currently working on profiling the constructs. The previously described in vitro and in vivo new experimental solutions can also be applied to study RNA/intracellular protein interactions, opening the way to innovative RNA-based therapeutics such as RNA-PROTAC. The nucleic acid based-PROTAC exploits known RNA binding motifs to tag RNA-binding proteins (RBP) for their selective degradation through the endogenous proteasomal machinery of cells.