Phosphorothioate-modified antisense oligonucleotide-binding proteins (PS-ASO binding proteins)

Phosphorothioate-modified antisense oligonucleotide (PS-ASO) binding proteins are a broad class of proteins that interact with the chemically modified sulfur-containing backbone of ASO therapeutics. This interaction is fundamental to the pharmacology of PS-ASOs, as binding to plasma proteins like albumin prevents rapid renal clearance and extends the half-life of the drug in circulation (Crooke et al., 2017, Nucleic Acids Res). Once inside the cell, PS-ASOs interact with a variety of intracellular proteins, including nucleolin, NONO (p54nrb), and SFPQ (PSF), which facilitate their trafficking between the cytoplasm and the nucleus (Liang et al., 2015, Nucleic Acids Res). While these interactions are necessary for the delivery and stability of the oligonucleotide, non-specific binding to certain proteins can lead to toxicities such as thrombocytopenia or nephrotoxicity (Shen et al., 2019, Nat Biotechnol). Furthermore, the recruitment of specific enzymes like Ribonuclease H1 (RNase H1) is essential for the catalytic degradation of target mRNA in gapmer-based ASO strategies. Consequently, the PS-ASO interactome is a critical factor in determining both the therapeutic index and the distribution of oligonucleotide-based medicines.

Other names

PS-ASO interactomePhosphorothioate-binding proteinsASO-interacting proteinsOligonucleotide-binding proteins

These proteins interact with the phosphorothioate (PS) backbone of antisense oligonucleotides to facilitate cellular uptake, protect against nuclease degradation, and mediate intracellular transport to the target RNA. Specific proteins like RNase H1 act as effectors to cleave the target mRNA upon ASO binding.