Phosphorothioate oligonucleotide-binding proteins (PS-BPs)

Phosphorothioate oligonucleotide-binding proteins are a heterogeneous group of plasma and cellular proteins that interact with phosphorothioate-modified antisense oligonucleotides (PS-ASOs), dictating their pharmacokinetics and cellular disposition. In the blood, PS-ASOs bind extensively to plasma proteins such as albumin and apolipoprotein A-I, which prevents rapid renal clearance and facilitates tissue distribution (Gaus et al., 2019). Cellular uptake is primarily mediated by interactions with cell-surface receptors, including scavenger receptors like SCARA1, which internalize the oligonucleotides through endocytosis. Within the cell, PS-ASOs interact with various proteins such as nucleolin, NONO (P54nrb), and SFPQ (PSF), which play roles in endosomal escape and trafficking to the nucleus or cytoplasm (Liang et al., 2015; Crooke et al., 2017). While these interactions are essential for the delivery and stability of ASO therapeutics, they can also lead to off-target toxicities, such as complement activation via Factor H binding or thrombocytopenia. Understanding the interaction between PS-ASOs and these proteins is vital for the design of safer and more effective oligonucleotide-based medicines.

Other names

PS-ASO binding proteinsPlasma and cellular PS-binding proteinsOligonucleotide-interacting proteins

Phosphorothioate oligonucleotides bind to these proteins via their modified backbone, which enhances plasma stability, facilitates receptor-mediated endocytosis, and modulates intracellular distribution to reach target RNA (Crooke et al., 2017; Gaus et al., 2019).