Challenges with osmolytes as inhibitors of protein aggregation: Can nucleic acid aptamers provide an answer?

Protein aggregation follows some common motifs. Whether in the formation of inclusion bodies in heterologous overexpression systems or inclusions in protein conformational diseases, or aggregation during storage or transport of protein formulations, aggregates form cross beta-sheet structures and stain with amyloidophilic dyes like Thioflavin T and Congo Red, irrespective of the concerned protein. Traditionally, osmolytes are used to stabilize proteins against stress conditions. They are employed right from protein expression, through production and purification, to formulation and administration. As osmolytes interact with the solvent, the differential effect of the stress condition on the solvent mostly determines the effect of the osmolyte on protein stability. Nucleic acid aptamers, on the other hand, are highly specific for their targets. When selected against monomeric, natively folded proteins, they bind to them with very high affinity. This binding inhibits the unfolding of the protein and/or monomer-monomer interaction which are the initial common steps of protein aggregation. Thus, by changing the approach to a protein-centric model, aptamers are able to function as universal stabilizers of proteins. The review discusses cases where osmolytes were unable to provide stabilization to proteins against different stress conditions, a gap which the aptamers seem to be able to fill.