Chemical Insights into Oligonucleotide–Protein Binding for Therapeutic Applications

Plasma protein binding is an important determinant in the clinical success of oligonucleotide-based drugs. Optimal protein binding of the oligonucleotide is critical to its tissue distribution and retention by preventing renal excretion. This property can be modulated through suitable chemical modifications depending on the oligonucleotide backbone to achieve a balanced pharmacokinetic profile and minimize off-target effects. The macromolecular structure of the oligonucleotide leads to dynamic protein binding characteristics as compared to small-molecule-based drugs, which are not associated with additional barriers such as intracellular delivery. This perspective provides insight into the diverse plasma protein interactions of various classes of oligonucleotides and explores chemical strategies for modulating these interactions. Furthermore, we have discussed different methods for the quantification of plasma protein binding along with the correlation of chemistry and therapeutic outcomes of FDA-approved oligonucleotides.